Genetic Variants Underlying Human Cognition and Methods of Use Thereof as Diagnostic and Therapeutic Targets

ABSTRACT

Compositions and methods for the detection and treatment of neurological disorders, including ASD, are provided.

This Application is a continuation application of U.S. application Ser.No. 14/501,006 filed Sep. 29, 2014 which is a divisional of U.S.application Ser. No. 13/129,526 filed Aug. 23, 2011, which is a § 371national phase entry of PCT/US2009/64617 filed Nov. 16, 2009, whichclaims priority to U.S. Provisional Application 61/114,921 filed Nov.14, 2008, each of the aforementioned applications being incorporatedherein by reference.

This invention was made with government support under Grant NumberP50HD055784-01 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

This invention relates to the fields of genetics and the diagnosis andtreatment of cognitive and neurological disorders. More specifically,the invention provides nucleic acids comprising copy number variations(CNVs) which are associated with the multiple disorders of humancognition and behavior and methods of use thereof in diagnostic andtherapeutic applications.

BACKGROUND OF THE INVENTION

Several publications and patent documents are cited throughout thespecification in order to describe the state of the art to which thisinvention pertains. Each of these citations is incorporated herein byreference as though set forth in full.

Neurologic diseases can result from disorders of the brain, spinal cordand nerves. Patients experiencing neurological disease may have troublemoving, speaking, swallowing, breathing or learning. Problems withmemory, senses behavior or mood are also associated with neurologicaldisorders. There are many different underlying causes of neurologicaldysfunction. These can include genetic mutation, exposure to toxicsubstances and injury.

There are more than 600 neurologic diseases. Major types includediseases caused by faulty genes, such as Huntington's disease andmuscular dystrophy; aberrant embryonal development of the nervoussystem, such as spina bifida; degenerative diseases, where nerve cellsare damaged or die, such as Parkinson's disease and Alzheimer's disease;diseases of the blood vessels that supply the brain, such as stroke;injuries to the spinal cord and brain; seizure disorders, such asepilepsy; cancer, such as brain tumors and infections, such asmeningitis.

Multiple disorders of human cognition and behavior appear to bemodulated by genetic factors. However, the manner by which geneticvariation impacts disease is complex and poorly understood. Similarlyelusive are the identity of specific genes that may be useful withregards to diagnosis and therapeutic intervention. It is an object ofthe invention to provide these genetic markers and to furthercharacterize the alterations therein that lead to a loss of cognitivefunction and neurological development.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method for detecting apropensity for developing a neurological disorder in a patient in needthereof is provided. An exemplary method entails detecting the presenceof at least one CNV containing nucleic acid in a target polynucleotidewherein if said CNV is present, said patient has an increased risk fordeveloping autism/ASD, wherein said CNV containing nucleic acid isselected from the group of CNVs that are either exclusive to orsignificantly overrepresented in neurological disorders, particularlyautism spectrum disorder. (see Tables 1, 3, and 6).

In another embodiment of the invention, a method for identifying agentswhich alter neuronal signaling and/or morphology is provided. Such amethod comprises providing cells expressing at least one of the CNVslisted above (step a); providing cells which express the cognate wildtype sequences corresponding to the CNV (step b); contacting the cellsfrom each sample with a test agent and analyzing whether said agentalters neuronal signaling and/or morphology of cells of step a) relativeto those of step b), thereby identifying agents which alter neuronalsignaling and morphology. Methods of treating patients having aneurological disorder via administration of pharmaceutical compositionscomprising agents identified using the methods described herein inpatients in need thereof are also encompassed by the present invention.

The invention also provides at least one isolated neurological disorderrelated CNV-containing nucleic acid selected from the group that areeither exclusive to or significantly overrepresented in neurologicaldisorders, particularly ASD (see Table 1 and Table 6 Such CNV containingnucleic acids may optionally be contained in a suitable expressionvector for expression in neuronal cells. Alternatively, they may beimmobilized on a solid support.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1—TaqMan experiments validate copy number calls determined byPennCNV. To validate results using an independent method we designedTaqMan assays to evaluate gene dosage. Results from representativeexperiments highlight results at loci at 1q21, 8q21, and 10q24. AGREindividual harboring deletions (arrows pointing downward) or gains(arrows pointing upwards) are indicated.

FIG. 2—Rare exonic deletions (eDels) in NRXN1 and novel candidate genesalter predicted protein structures. For each of NRXN1 (a), CLCKNKA (b),GRIK5 (c), and GMPS (d) reference loci and encoded proteins (top) arecontrasted against mutant loci and proteins (bottom; grey shading).Unique genomic deletions and corresponding protein truncations areshown. Schematized protein domains genes are as follows: NRXN1 Laminin G(hexagon), EGF-like (oval), 4.1 binding motif (rectangle);CLCNKA—Chloride channel, core (rectangle), Cystathionine beta-synthase,core (pentagon); GRIK5 Extracellular ligand-binding receptor (oval),Ionotropic glutamate receptor (hexagon); GMPS—Glutamine amidotransferaseclass-I, C-terminal (rectangle), Exoenzyme S synthesis proteinB/queuosine synthesis (rectangle), (GMP synthase, C-terminal(rectangle). Rare exonic deletions (eDels) in NRXN1 and novel candidategenes alter predicted protein structures. For each of BZRAP1 and MDGA2(c) reference loci and encoded proteins (top) are contrasted againstmutant loci and corresponding proteins (bottom; grey shading). Uniquegenomic deletions and corresponding protein truncations are shown.Schematized protein domains genes are as follows: BZRAP1—Src homology-3(square), Fibronectin, type III (oval); MDGA2-IG-like domains(pentagon), MAM aka Meprin/A5-protein/PTPmu (oval).

FIG. 3—Multi-dimensional scaling plot of AGRE affected subjects, withcross highlighting subjects carrying the eDels. Subjects of Europeanancestry are clustered toward the right side of the triangle.

FIG. 4A—Observed replication unlikely to be attributable to chancealone. We performed 10,000 phenotype permutation trials on replicationdata and determined for each the number of loci harboring CNVs in casesbut not controls. Thus, within each trial, the number of loci absentfrom controls in the replication cohort was determined. None of thepermutation trials generated as many case-specific loci as observed inour actual dataset (n=14; p<0.0001). FIG. 4B. We also performed 10,000phenotype permutation trials on replication data and determined for eachthe number of loci harboring CNVs exclusively in controls. During eachtrial a new set of control-specific loci was identified and the numberof these absent from cases determined. We observed results comparable tothose obtained experimentally (n=18) in 246 of 10,000 trials (p=0.02)

FIG. 5—Exonic deletions, although enriched in cases versus controls,show imperfect segregation with disease in multiplex families. Pedigreesfor representative AGRE families harboring exonic deletions in BZRAP1(A,B), kb), NRXN1 (C,D), and MDGA2 (E,F) are illustrated. Filled circlescorrespond to exonic deletions. Black stars (upper right) highlightindividuals for which CNV calls were not obtained (not genotyped orfailing to meet criteria for quality control).

DETAILED DESCRIPTION OF THE INVENTION

The genetics underlying the neurological disorders (e.g., autism, autismspectrum disorder (ASD) schizophrenia, bipolar disorder, Tourette'ssyndrome, obsessive compulsive disorder (OCD) is highly complex andremains poorly understood. Previous work has demonstrated an importantrole for structural variation in a subset of cases, but the analysislacked the resolution necessary to move beyond detection of largeregions of potential interest to identification of individual genes.Autism spectrum disorders (ASDs) are common neurodevelopmental syndromeswith a strong genetic component. ASDs are characterized by disturbancesin social behavior, impaired verbal and nonverbal communication, as wellas repetitive behaviors and/or a restricted range of interests. Toidentify genes likely to contribute to ASD etiology, we performed highdensity genotyping in 912 multiplex families from the Autism GeneticsResource Exchange (AGRE) collection and contrasted results to thoseobtained for 1,488 healthy controls. To enrich for variants most likelyto interfere with gene function, we restricted our analyses to deletionsand gains encompassing exons. Of the many genomic regions highlighted,27 were seen to harbor rare variants in cases and not controls, both inthe first phase of our analysis, and also in an independent replicationcohort comprised of 859 cases and 1,051 controls. The genes identifiedby this method include NRXN1, a molecule in which rare ASD-relatedvariation has been well documented by multiple groups. We findcomparable support for several genes not previously implicated in theASDs, including BZRAP1, MDGA2, CLCNKA, GRIK5 and GMPS. For each ofthese, mutant alleles eliminate entirely or remove the majority ofprotein coding sequences. Importantly, interrogation of an independentlyascertained and non-overlapping ASD cohort identified eDels in thesesame genes in almost a third of cases, a result unlikely to occur bychance alone (p=1×10⁻³⁶ by Fisher Exact). These newly identified autismsusceptibility genes will be useful in understanding key signalingpathways dysregulated in this group of disorders.

Definitions

A “copy number variation (CNV)” refers to the number of copies of aparticular gene in the genotype of an individual. CNVs represent a majorgenetic component of human phenotypic diversity. Susceptibility togenetic disorders is known to be associated not only with singlenucleotide polymorphisms (CNV), but also with structural and othergenetic variations, including CNVs. A CNV represents a copy numberchange involving a DNA fragment that is ˜1 kilobases (kb) or larger(Feuk et al. 2006 Nature. 444:444-54.). CNVs described herein do notinclude those variants that arise from the insertion/deletion oftransposable elements (e.g., ˜6-kb KpnI repeats) to minimize thecomplexity of future CNV analyses. The term CNV therefore encompassespreviously introduced terms such as large-scale copy number variants(LCVs; Iafrate et al. 2004, Nature Genetics 36: 949-51), copy numberpolymorphisms (CNPs; Sebat et al. 2004 Science 305:525-8),intermediate-sized variants (ISVs; Tuzun et al. 2006 Genome Res. 16:949-961), and eDELs, but not retroposon insertions.

A “single nucleotide polymorphism (SNP)” refers to a change in which asingle base in the DNA differs from the usual base at that position.These single base changes are called SNPs or “snips.” Millions of SNPshave been cataloged in the human genome. Some SNPs such as that whichcauses sickle cell are responsible for disease. Other SNPs are normalvariations in the genome.

A neurological disorder includes, without limitation, schizophrenia,bipolar disorder, autism, autism spectrum disorder (ASD), TouretteSyndrome, and obsessive compulsive disorder.

The term “genetic alteration” which encompasses a CNV or SNP as definedabove, refers to a change from the wild-type or reference sequence ofone or more nucleic acid molecules. Genetic alterations include withoutlimitation, base pair substitutions, additions and deletions of at leastone nucleotide from a nucleic acid molecule of known sequence.

The term “solid matrix” as used herein refers to any format, such asbeads, microparticles, a microarray, the surface of a microtitrationwell or a test tube, a dipstick or a filter. The material of the matrixmay be polystyrene, cellulose, latex, nitrocellulose, nylon,polyacrylamide, dextran or agarose.

The phrase “consisting essentially of” when referring to a particularnucleotide or amino acid means a sequence having the properties of agiven SEQ ID NO. For example, when used in reference to an amino acidsequence, the phrase includes the sequence per se and molecularmodifications that would not affect the functional and novelcharacteristics of the sequence.

“Target nucleic acid” as used herein refers to a previously definedregion of a nucleic acid present in a complex nucleic acid mixturewherein the defined wild-type region contains at least one knownnucleotide variation which may or may not be associated withneurological disorder. The nucleic acid molecule may be isolated from anatural source by cDNA cloning or subtractive hybridization orsynthesized manually. The nucleic acid molecule may be synthesizedmanually by the triester synthetic method or by using an automated DNAsynthesizer. With regard to nucleic acids used in the invention, theterm “isolated nucleic acid” is sometimes employed. This term, whenapplied to DNA, refers to a DNA molecule that is separated fromsequences with which it is immediately contiguous (in the 5′ and 3′directions) in the naturally occurring genome of the organism from whichit was derived. For example, the “isolated nucleic acid” may comprise aDNA molecule inserted into a vector, such as a plasmid or virus vector,or integrated into the genomic DNA of a prokaryote or eukaryote. An“isolated nucleic acid molecule” may also comprise a cDNA molecule. Anisolated nucleic acid molecule inserted into a vector is also sometimesreferred to herein as a recombinant nucleic acid molecule.

With respect to RNA molecules, the term “isolated nucleic acid”primarily refers to an RNA molecule encoded by an isolated DNA moleculeas defined above. Alternatively, the term may refer to an RNA moleculethat has been sufficiently separated from RNA molecules with which itwould be associated in its natural state (i.e., in cells or tissues),such that it exists in a “substantially pure” form.

By the use of the term “enriched” in reference to nucleic acid it ismeant that the specific DNA or RNA sequence constitutes a significantlyhigher fraction (2-5 fold) of the total DNA or RNA present in the cellsor solution of interest than in normal cells or in the cells from whichthe sequence was taken. This could be caused by a person by preferentialreduction in the amount of other DNA or RNA present, or by apreferential increase in the amount of the specific DNA or RNA sequence,or by a combination of the two. However, it should be noted that“enriched” does not imply that there are no other DNA or RNA sequencespresent, just that the relative amount of the sequence of interest hasbeen significantly increased.

It is also advantageous for some purposes that a nucleotide sequence bein purified form. The term “purified” in reference to nucleic acid doesnot require absolute purity (such as a homogeneous preparation);instead, it represents an indication that the sequence is relativelypurer than in the natural environment (compared to the natural level,this level should be at least 2-5 fold greater, e.g., in terms ofmg/ml). Individual clones isolated from a cDNA library may be purifiedto electrophoretic homogeneity. The claimed DNA molecules obtained fromthese clones can be obtained directly from total DNA or from total RNA.The cDNA clones are not naturally occurring, but rather are preferablyobtained via manipulation of a partially purified naturally occurringsubstance (messenger RNA). The construction of a cDNA library from mRNAinvolves the creation of a synthetic substance (cDNA) and pureindividual cDNA clones can be isolated from the synthetic library byclonal selection of the cells carrying the cDNA library. Thus, theprocess which includes the construction of a cDNA library from mRNA andisolation of distinct cDNA clones yields an approximately 10⁻⁶-foldpurification of the native message. Thus, purification of at least oneorder of magnitude, preferably two or three orders, and more preferablyfour or five orders of magnitude is expressly contemplated.

The term “substantially pure” refers to a preparation comprising atleast 50-60% by weight the compound of interest (e.g., nucleic acid,oligonucleotide, etc.). More preferably, the preparation comprises atleast 75% by weight, and most preferably 90-99% by weight, the compoundof interest. Purity is measured by methods appropriate for the compoundof interest.

The term “complementary” describes two nucleotides that can formmultiple favorable interactions with one another. For example, adenineis complementary to thymine as they can form two hydrogen bonds.Similarly, guanine and cytosine are complementary since they can formthree hydrogen bonds. Thus, if a nucleic acid sequence contains thefollowing sequence of bases, thymine, adenine, guanine and cytosine, a“complement” of this nucleic acid molecule would be a moleculecontaining adenine in the place of thymine, thymine in the place ofadenine, cytosine in the place of guanine, and guanine in the place ofcytosine. Because the complement can contain a nucleic acid sequencethat forms optimal interactions with the parent nucleic acid molecule,such a complement can bind with high affinity to its parent molecule.

With respect to single stranded nucleic acids, particularlyoligonucleotides, the term “specifically hybridizing” refers to theassociation between two single-stranded nucleotide molecules ofsufficiently complementary sequence to permit such hybridization underpre-determined conditions generally used in the art (sometimes termed“substantially complementary”). In particular, the term refers tohybridization of an oligonucleotide with a substantially complementarysequence contained within a single-stranded DNA or RNA molecule of theinvention, to the substantial exclusion of hybridization of theoligonucleotide with single-stranded nucleic acids of non-complementarysequence. For example, specific hybridization can refer to a sequencewhich hybridizes to any neurological disorder specific marker gene ornucleic acid, but does not hybridize to other nucleotides. Alsopolynucleotide which “specifically hybridizes” may hybridize only to aneurospecific specific marker, such a neurological disorder-specificmarker shown in the Tables contained herein. Appropriate conditionsenabling specific hybridization of single stranded nucleic acidmolecules of varying complementarity are well known in the art.

For instance, one common formula for calculating the stringencyconditions required to achieve hybridization between nucleic acidmolecules of a specified sequence homology is set forth below (Sambrooket al., Molecular Cloning, Cold Spring Harbor Laboratory (1989):

T_(m)=81.5″C+16.6 Log[Na+]+0.41(% G+C)−0.63(% formamide)−600/#bp induplex

As an illustration of the above formula, using [Na+]=[0.368] and 50%formamide, with GC content of 42% and an average probe size of 200bases, the T_(m) is 57″C. The T_(m) of a DNA duplex decreases by 1-1.5″Cwith every 1% decrease in homology. Thus, targets with greater thanabout 75% sequence identity would be observed using a hybridizationtemperature of 42″C.

The stringency of the hybridization and wash depend primarily on thesalt concentration and temperature of the solutions. In general, tomaximize the rate of annealing of the probe with its target, thehybridization is usually carried out at salt and temperature conditionsthat are 20-25° C. below the calculated T_(m) of the hybrid. Washconditions should be as stringent as possible for the degree of identityof the probe for the target. In general, wash conditions are selected tobe approximately 12-20° C. below the T_(m) of the hybrid. In regards tothe nucleic acids of the current invention, a moderate stringencyhybridization is defined as hybridization in 6×SSC, 5×Denhardt'ssolution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C.,and washed in 2×SSC and 0.5% SDS at 55° C. for 15 minutes. A highstringency hybridization is defined as hybridization in 6×SSC,5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNAat 42° C., and washed in 1×SSC and 0.5% SDS at 65° C. for 15 minutes. Avery high stringency hybridization is defined as hybridization in 6×SSC,5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNAat 42° C., and washed in 0.1×SSC and 0.5% SDS at 65° C. for 15 minutes.

The term “oligonucleotide,” as used herein is defined as a nucleic acidmolecule comprised of two or more ribo- or deoxyribonucleotides,preferably more than three. The exact size of the oligonucleotide willdepend on various factors and on the particular application and use ofthe oligonucleotide. Oligonucleotides, which include probes and primers,can be any length from 3 nucleotides to the full length of the nucleicacid molecule, and explicitly include every possible number ofcontiguous nucleic acids from 3 through the full length of thepolynucleotide. Preferably, oligonucleotides are at least about 10nucleotides in length, more preferably at least 15 nucleotides inlength, more preferably at least about 20 nucleotides in length.

The term “probe” as used herein refers to an oligonucleotide,polynucleotide or nucleic acid, either RNA or DNA, whether occurringnaturally as in a purified restriction enzyme digest or producedsynthetically, which is capable of annealing with or specificallyhybridizing to a nucleic acid with sequences complementary to the probe.A probe may be either single-stranded or double-stranded. The exactlength of the probe will depend upon many factors, includingtemperature, source of probe and use of the method. For example, fordiagnostic applications, depending on the complexity of the targetsequence, the oligonucleotide probe typically contains 15-25 or morenucleotides, although it may contain fewer nucleotides. The probesherein are selected to be complementary to different strands of aparticular target nucleic acid sequence. This means that the probes mustbe sufficiently complementary so as to be able to “specificallyhybridize” or anneal with their respective target strands under a set ofpre-determined conditions. Therefore, the probe sequence need notreflect the exact complementary sequence of the target. For example, anon-complementary nucleotide fragment may be attached to the 5′ or 3′end of the probe, with the remainder of the probe sequence beingcomplementary to the target strand. Alternatively, non-complementarybases or longer sequences can be interspersed into the probe, providedthat the probe sequence has sufficient complementarity with the sequenceof the target nucleic acid to anneal therewith specifically.

The term “primer” as used herein refers to an oligonucleotide, eitherRNA or DNA, either single-stranded or double-stranded, either derivedfrom a biological system, generated by restriction enzyme digestion, orproduced synthetically which, when placed in the proper environment, isable to functionally act as an initiator of template-dependent nucleicacid synthesis. When presented with an appropriate nucleic acidtemplate, suitable nucleoside triphosphate precursors of nucleic acids,a polymerase enzyme, suitable cofactors and conditions such as asuitable temperature and pH, the primer may be extended at its 3′terminus by the addition of nucleotides by the action of a polymerase orsimilar activity to yield a primer extension product. The primer mayvary in length depending on the particular conditions and requirement ofthe application. For example, in diagnostic applications, theoligonucleotide primer is typically 15-25 or more nucleotides in length.The primer must be of sufficient complementarity to the desired templateto prime the synthesis of the desired extension product, that is, to beable anneal with the desired template strand in a manner sufficient toprovide the 3′ hydroxyl moiety of the primer in appropriatejuxtaposition for use in the initiation of synthesis by a polymerase orsimilar enzyme. It is not required that the primer sequence represent anexact complement of the desired template. For example, anon-complementary nucleotide sequence may be attached to the 5′ end ofan otherwise complementary primer. Alternatively, non-complementarybases may be interspersed within the oligonucleotide primer sequence,provided that the primer sequence has sufficient complementarity withthe sequence of the desired template strand to functionally provide atemplate-primer complex for the synthesis of the extension product.Polymerase chain reaction (PCR) has been described in U.S. Pat. Nos.4,683,195, 4,800,195, and 4,965,188, the entire disclosures of which areincorporated by reference herein.

The term “vector” relates to a single or double stranded circularnucleic acid molecule that can be infected, transfected or transformedinto cells and replicate independently or within the host cell genome. Acircular double stranded nucleic acid molecule can be cut and therebylinearized upon treatment with restriction enzymes. An assortment ofvectors, restriction enzymes, and the knowledge of the nucleotidesequences that are targeted by restriction enzymes are readily availableto those skilled in the art, and include any replicon, such as aplasmid, cosmid, bacmid, phage or virus, to which another geneticsequence or element (either DNA or RNA) may be attached so as to bringabout the replication of the attached sequence or element. A nucleicacid molecule of the invention can be inserted into a vector by cuttingthe vector with restriction enzymes and ligating the two piecestogether.

Many techniques are available to those skilled in the art to facilitatetransformation, transfection, or transduction of the expressionconstruct into a prokaryotic or eukaryotic organism. The terms“transformation”, “transfection”, and “transduction” refer to methods ofinserting a nucleic acid and/or expression construct into a cell or hostorganism. These methods involve a variety of techniques, such astreating the cells with high concentrations of salt, an electric field,or detergent, to render the host cell outer membrane or wall permeableto nucleic acid molecules of interest, microinjection, PEG-fusion, andthe like.

The term “promoter element” describes a nucleotide sequence that isincorporated into a vector that, once inside an appropriate cell, canfacilitate transcription factor and/or polymerase binding and subsequenttranscription of portions of the vector DNA into mRNA. In oneembodiment, the promoter element of the present invention precedes the5′ end of the neurological disorder specific marker nucleic acidmolecule such that the latter is transcribed into mRNA. Host cellmachinery then translates mRNA into a polypeptide.

Those skilled in the art will recognize that a nucleic acid vector cancontain nucleic acid elements other than the promoter element and theneurological disorder specific marker gene nucleic acid molecule. Theseother nucleic acid elements include, but are not limited to, origins ofreplication, ribosomal binding sites, nucleic acid sequences encodingdrug resistance enzymes or amino acid metabolic enzymes, and nucleicacid sequences encoding secretion signals, localization signals, orsignals useful for polypeptide purification.

A “replicon” is any genetic element, for example, a plasmid, cosmid,bacmid, plastid, phage or virus, that is capable of replication largelyunder its own control. A replicon may be either RNA or DNA and may besingle or double stranded.

An “expression operon” refers to a nucleic acid segment that may possesstranscriptional and translational control sequences, such as promoters,enhancers, translational start signals (e.g., ATG or AUG codons),polyadenylation signals, terminators, and the like, and which facilitatethe expression of a polypeptide coding sequence in a host cell ororganism.

As used herein, the terms “reporter,” “reporter system”, “reportergene,” or “reporter gene product” shall mean an operative genetic systemin which a nucleic acid comprises a gene that encodes a product thatwhen expressed produces a reporter signal that is a readily measurable,e.g., by biological assay, immunoassay, radio immunoassay, or bycolorimetric, fluorogenic, chemiluminescent or other methods. Thenucleic acid may be either RNA or DNA, linear or circular, single ordouble stranded, antisense or sense polarity, and is operatively linkedto the necessary control elements for the expression of the reportergene product. The required control elements will vary according to thenature of the reporter system and whether the reporter gene is in theform of DNA or RNA, but may include, but not be limited to, suchelements as promoters, enhancers, translational control sequences, polyA addition signals, transcriptional termination signals and the like.

The introduced nucleic acid may or may not be integrated (covalentlylinked) into nucleic acid of the recipient cell or organism. Inbacterial, yeast, plant and mammalian cells, for example, the introducednucleic acid may be maintained as an episomal element or independentreplicon such as a plasmid. Alternatively, the introduced nucleic acidmay become integrated into the nucleic acid of the recipient cell ororganism and be stably maintained in that cell or organism and furtherpassed on or inherited to progeny cells or organisms of the recipientcell or organism. Finally, the introduced nucleic acid may exist in therecipient cell or host organism only transiently.

The term “selectable marker gene” refers to a gene that when expressedconfers a selectable phenotype, such as antibiotic resistance, on atransformed cell.

The term “operably linked” means that the regulatory sequences necessaryfor expression of the coding sequence are placed in the DNA molecule inthe appropriate positions relative to the coding sequence so as toeffect expression of the coding sequence. This same definition issometimes applied to the arrangement of transcription units and othertranscription control elements (e.g. enhancers) in an expression vector.

The terms “recombinant organism,” or “transgenic organism” refer toorganisms which have a new combination of genes or nucleic acidmolecules. A new combination of genes or nucleic acid molecules can beintroduced into an organism using a wide array of nucleic acidmanipulation techniques available to those skilled in the art. The term“organism” relates to any living being comprised of a least one cell. Anorganism can be as simple as one eukaryotic cell or as complex as amammal. Therefore, the phrase “a recombinant organism” encompasses arecombinant cell, as well as eukaryotic and prokaryotic organism.

The term “isolated protein” or “isolated and purified protein” issometimes used herein. This term refers primarily to a protein producedby expression of an isolated nucleic acid molecule of the invention.Alternatively, this term may refer to a protein that has beensufficiently separated from other proteins with which it would naturallybe associated, so as to exist in “substantially pure” form. “Isolated”is not meant to exclude artificial or synthetic mixtures with othercompounds or materials, or the presence of impurities that do notinterfere with the fundamental activity, and that may be present, forexample, due to incomplete purification, addition of stabilizers, orcompounding into, for example, immunogenic preparations orpharmaceutically acceptable preparations.

A “specific binding pair” comprises a specific binding member (sbm) anda binding partner (bp) which have a particular specificity for eachother and which in normal conditions bind to each other in preference toother molecules. Examples of specific binding pairs are antigens andantibodies, ligands and receptors and complementary nucleotidesequences. The skilled person is aware of many other examples. Further,the term “specific binding pair” is also applicable where either or bothof the specific binding member and the binding partner comprise a partof a large molecule. In embodiments in which the specific binding paircomprises nucleic acid sequences, they will be of a length to hybridizeto each other under conditions of the assay, preferably greater than 10nucleotides long, more preferably greater than 15 or 20 nucleotideslong.

“Sample” or “patient sample” or “biological sample” generally refers toa sample which may be tested for a particular molecule, preferably aneurological disorder specific marker molecule, such as a marker shownin the tables provided below. Samples may include but are not limited tocells, body fluids, including blood, serum, plasma, urine, saliva,tears, pleural fluid and the like.

The terms “agent” and “test compound” are used interchangeably hereinand denote a chemical compound, a mixture of chemical compounds, abiological macromolecule, or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Biological macromolecules include siRNA, shRNA,antisense oligonucleotides, peptides, peptide/DNA complexes, and anynucleic acid based molecule which exhibits the capacity to modulate theactivity of the CNV containing nucleic acids described herein or theirencoded proteins. Agents are evaluated for potential biological activityby inclusion in screening assays described hereinbelow.

Methods of Using Neurological Disorder-Associated eCNVS for Diagnosingan Increased Risk for the Development of a Neurological Disorder

Neurological disorder-related-eCNV containing nucleic acids, includingbut not limited to those listed in the Tables provided below may be usedfor a variety of purposes in accordance with the present invention.Neurological disorder-associated eCNV containing DNA, RNA, or fragmentsthereof may be used as probes to detect the presence of and/orexpression of neurological disorder specific markers. Methods in whichneurological disorder specific marker nucleic acids may be utilized asprobes for such assays include, but are not limited to: (1) in situhybridization; (2) Southern hybridization (3) northern hybridization;and (4) assorted amplification reactions such as polymerase chainreactions (PCR).

Further, assays for detecting neurological disorder-associated eCNVs maybe conducted on any type of biological sample, including but not limitedto body fluids (including blood, CSF, urine, serum, gastric lavage), anytype of cell (such as brain cells, white blood cells, mononuclear cells)or body tissue.

From the foregoing discussion, it can be seen that neurologicaldisorder-associated eCNV containing nucleic acids, vectors expressingthe same, neurological disorder eCNV containing marker proteins andanti-neurological disorder specific marker antibodies of the inventioncan be used to detect neurological disorder associated eCNVs in bodytissue, cells, or fluid, and alter neurological disorder eCNV containingmarker protein expression for purposes of assessing the genetic andprotein interactions involved in the development of neurologicaldisorder.

In most embodiments for screening for neurological disorder-associatedCNVs, the neurological disorder-associated CNV containing nucleic acidin the sample will initially be amplified, e.g. using PCR, to increasethe amount of the templates as compared to other sequences present inthe sample. This allows the target sequences to be detected with a highdegree of sensitivity if they are present in the sample. This initialstep may be avoided by using highly sensitive array techniques that arebecoming increasingly important in the art.

Alternatively, new detection technologies can overcome this limitationand enable analysis of small samples containing as little as 1 μg oftotal RNA. Using Resonance Light Scattering (RLS) technology, as opposedto traditional fluorescence techniques, multiple reads can detect lowquantities of mRNAs using biotin labeled hybridized targets andanti-biotin antibodies. Another alternative to PCR amplificationinvolves planar wave guide technology (PWG) to increase signal-to-noiseratios and reduce background interference. Both techniques arecommercially available from Qiagen Inc. (USA).

Thus any of the aforementioned techniques may be used to detect orquantify neurological disorder-associated CNV marker expression andaccordingly, diagnose neurological disorder(s).

Kits and Articles of Manufacture

Any of the aforementioned products can be incorporated into a kit whichmay contain a neurological disorder-associated CNV specific markerpolynucleotide or one or more such markers immobilized on a Gene Chip,an oligonucleotide, a polypeptide, a peptide, an antibody, a label,marker, or reporter, a pharmaceutically acceptable carrier, aphysiologically acceptable carrier, instructions for use, a container, avessel for administration, an assay substrate, enzyme, or anycombination thereof.

Methods of Using Neurological Disorder-Associated CNVs/SNPs Developmentof Therapeutic Agents

Since the CNVs identified herein have been associated with the etiologyof a neurological disorder, methods for identifying agents that modulatethe activity of the genes and their encoded products containing suchCNVs should result in the generation of efficacious therapeutic agentsfor the treatment of such conditions.

As can be seen from the data provided in the Tables below, severalchromosomes contain regions which provide suitable targets for therational design of therapeutic agents which modulate their activity.Specific organic molecules can thus be identified with capacity to bindto the active site of the proteins encoded by the CNV containing nucleicacids based on conformation or key amino acid residues required forfunction. A combinatorial chemistry approach will be used to identifymolecules with greatest activity and then iterations of these moleculeswill be developed for further cycles of screening. In certainembodiments, candidate agents can be screening from large libraries ofsynthetic or natural compounds. Such compound libraries are commerciallyavailable from a number of companies including but not limited toMaybridge Chemical Co., (Trevillet, Cornwall, UK), Comgenex (Princeton,N.J.), Microsour (New Milford, Conn.) Aldrich (Milwaukee, Wis.) AkosConsulting and Solutions GmbH (Basel, Switzerland), Ambinter (Paris,France), Asinex (Moscow, Russia) Aurora (Graz, Austria), BioFocus DPI(Switzerland), Bionet (Camelford, UK), Chembridge (San Diego, Calif.),Chem Div (San Diego, Calif.). The skilled person is aware of othersources and can readily purchase the same. Once therapeuticallyefficacious compounds are identified in the screening assays describedherein, they can be formulated in to pharmaceutical compositions andutilized for the treatment of a neurological disorder.

The polypeptides or fragments employed in drug screening assays mayeither be free in solution, affixed to a solid support or within a cell.One method of drug screening utilizes eukaryotic or prokaryotic hostcells which are stably transformed with recombinant polynucleotidesexpressing the polypeptide or fragment, preferably in competitivebinding assays. Such cells, either in viable or fixed form, can be usedfor standard binding assays. One may determine, for example, formationof complexes between the polypeptide or fragment and the agent beingtested, or examine the degree to which the formation of a complexbetween the polypeptide or fragment and a known substrate is interferedwith by the agent being tested.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity for the encodedpolypeptides and is described in detail in Geysen, PCT publishedapplication WO 84/03564, published on Sep. 13, 1984. Briefly stated,large numbers of different, small peptide test compounds, such as thosedescribed above, are synthesized on a solid substrate, such as plasticpins or some other surface. The peptide test compounds are reacted withthe target polypeptide and washed. Bound polypeptide is then detected bymethods well known in the art.

A further technique for drug screening involves the use of hosteukaryotic cell lines or cells (such as described above) which have anonfunctional or altered neurological disorder associated gene. Thesehost cell lines or cells are defective at the polypeptide level. Thehost cell lines or cells are grown in the presence of drug compound. Therate of neuronal signaling, ion release, or maintenance of neuronal cellmorphology of the host cells is measured to determine if the compound iscapable of regulating the same in the defective cells. Host cellscontemplated for use in the present invention include but are notlimited to bacterial cells, fungal cells, insect cells, and mammaliancells, particularly neuronal cells. The neurological disorder-associatedCNV encoding DNA molecules may be introduced singly into such host cellsor in combination to assess the phenotype of cells conferred by suchexpression. Methods for introducing DNA molecules are also well known tothose of ordinary skill in the art. Such methods are set forth inAusubel et al. eds., Current Protocols in Molecular Biology, John Wiley& Sons, NY, N.Y. 1995, the disclosure of which is incorporated byreference herein.

A wide variety of expression vectors are available that can be modifiedto express the novel DNA sequences of this invention. The specificvectors exemplified herein are merely illustrative, and are not intendedto limit the scope of the invention. Expression methods are described bySambrook et al. Molecular Cloning: A Laboratory Manual or CurrentProtocols in Molecular Biology 16.3-17.44 (1989). Expression methods inSaccharomyces are also described in Current Protocols in MolecularBiology (1989).

Suitable vectors for use in practicing the invention include prokaryoticvectors such as the pNH vectors (Stratagene Inc., 11099 N. Torrey PinesRd., La Jolla, Calif. 92037), pET vectors (Novogen Inc., 565 ScienceDr., Madison, Wis. 53711) and the pGEX vectors (Pharmacia LKBBiotechnology Inc., Piscataway, N.J. 08854). Examples of eukaryoticvectors useful in practicing the present invention include the vectorspRc/CMV, pRc/RSV, and pREP (Invitrogen, 11588 Sorrento Valley Rd., SanDiego, Calif. 92121); pcDNA3.1/V5&His (Invitrogen); baculovirus vectorssuch as pVL1392, pVL1393, or pAC360 (Invitrogen); and yeast vectors suchas YRP17, YIPS, and YEP24 (New England Biolabs, Beverly, Mass.), as wellas pRS403 and pRS413 Stratagene Inc.); Picchia vectors such as pHIL-D1(Phillips Petroleum Co., Bartlesville, Okla. 74004); retroviral vectorssuch as PLNCX and pLPCX (Clontech); and adenoviral and adeno-associatedviral vectors.

Promoters for use in expression vectors of this invention includepromoters that are operable in prokaryotic or eukaryotic cells.Promoters that are operable in prokaryotic cells include lactose (lac)control elements, bacteriophage lambda (pL) control elements, arabinosecontrol elements, tryptophan (trp) control elements, bacteriophage T7control elements, and hybrids thereof. Promoters that are operable ineukaryotic cells include Epstein Barr virus promoters, adenoviruspromoters, SV40 promoters, Rous Sarcoma Virus promoters, cytomegalovirus(CMV) promoters, baculovirus promoters such as AcMNPV polyhedrinpromoter, Picchia promoters such as the alcohol oxidase promoter, andSaccharomyces promoters such as the ga14 inducible promoter and the PGKconstitutive promoter, as well as neuronal-specific platelet-derivedgrowth factor promoter (PDGF), the Thy-1 promoter, the hamster and mousePrion promoter (MoPrP), and the Glial fibrillar acidic protein (GFAP)for the expression of transgenes in glial cells.

In addition, a vector of this invention may contain any one of a numberof various markers facilitating the selection of a transformed hostcell. Such markers include genes associated with temperaturesensitivity, drug resistance, or enzymes associated with phenotypiccharacteristics of the host organisms.

Host cells expressing the neurological disorder-associated CNVs of thepresent invention or functional fragments thereof provide a system inwhich to screen potential compounds or agents for the ability tomodulate the development of neurological disorder. Thus, in oneembodiment, the nucleic acid molecules of the invention may be used tocreate recombinant cell lines for use in assays to identify agents whichmodulate aspects of cellular metabolism associated with neuronalsignaling and neuronal cell communication and structure. Also providedherein are methods to screen for compounds capable of modulating thefunction of proteins encoded by CNV containing nucleic acids.

Another approach entails the use of phage display libraries engineeredto express fragment of the polypeptides encoded by the CNV containingnucleic acids on the phage surface. Such libraries are then contactedwith a combinatorial chemical library under conditions wherein bindingaffinity between the expressed peptide and the components of thechemical library may be detected. U.S. Pat. Nos. 6,057,098 and 5,965,456provide methods and apparatus for performing such assays.

The goal of rational drug design is to produce structural analogs ofbiologically active polypeptides of interest or of small molecules withwhich they interact (e.g., agonists, antagonists, inhibitors) in orderto fashion drugs which are, for example, more active or stable forms ofthe polypeptide, or which, e.g., enhance or interfere with the functionof a polypeptide in vivo. See, e.g., Hodgson, (1991) Bio/Technology9:19-21. In one approach, discussed above, the three-dimensionalstructure of a protein of interest or, for example, of theprotein-substrate complex, is solved by x-ray crystallography, bynuclear magnetic resonance, by computer modeling or most typically, by acombination of approaches. Less often, useful information regarding thestructure of a polypeptide may be gained by modeling based on thestructure of homologous proteins. An example of rational drug design isthe development of HIV protease inhibitors (Erickson et al., (1990)Science 249:527-533). In addition, peptides may be analyzed by analanine scan (Wells, (1991) Meth. Enzym. 202:390-411). In thistechnique, an amino acid residue is replaced by Ala, and its effect onthe peptide's activity is determined. Each of the amino acid residues ofthe peptide is analyzed in this manner to determine the importantregions of the peptide.

It is also possible to isolate a target-specific antibody, selected by afunctional assay, and then to solve its crystal structure. In principle,this approach yields a pharmacore upon which subsequent drug design canbe based.

One can bypass protein crystallography altogether by generatinganti-idiotypic antibodies (anti-ids) to a functional, pharmacologicallyactive antibody. As a mirror image of a mirror image, the binding siteof the anti-ids would be expected to be an analog of the originalmolecule. The anti-id could then be used to identify and isolatepeptides from banks of chemically or biologically produced banks ofpeptides. Selected peptides would then act as the pharmacore.

Thus, one may design drugs which have, e.g., improved polypeptideactivity or stability or which act as inhibitors, agonists, antagonists,etc. of polypeptide activity. By virtue of the availability of CNVcontaining nucleic acid sequences described herein, sufficient amountsof the encoded polypeptide may be made available to perform suchanalytical studies as x-ray crystallography. In addition, the knowledgeof the protein sequence provided herein will guide those employingcomputer modeling techniques in place of, or in addition to x-raycrystallography.

In another embodiment, the availability of neurologicaldisorder-associated CNV containing nucleic acids enables the productionof strains of laboratory mice carrying the neurologicaldisorder-associated CNVs of the invention. Transgenic mice expressingthe neurological disorder-associated CNV of the invention provide amodel system in which to examine the role of the protein encoded by theCNV containing nucleic acid in the development and progression towardsneurological disorder(s). Methods of introducing transgenes inlaboratory mice are known to those of skill in the art. Three commonmethods include: 1. integration of retroviral vectors encoding theforeign gene of interest into an early embryo; 2. injection of DNA intothe pronucleus of a newly fertilized egg; and 3. the incorporation ofgenetically manipulated embryonic stem cells into an early embryo.Production of the transgenic mice described above will facilitate themolecular elucidation of the role that a target protein plays in variouscellular metabolic and neuronal processes. Such mice provide an in vivoscreening tool to study putative therapeutic drugs in a whole animalmodel and are encompassed by the present invention.

The term “animal” is used herein to include all vertebrate animals,except humans. It also includes an individual animal in all stages ofdevelopment, including embryonic and fetal stages. A “transgenic animal”is any animal containing one or more cells bearing genetic informationaltered or received, directly or indirectly, by deliberate geneticmanipulation at the subcellular level, such as by targeted recombinationor microinjection or infection with recombinant virus. The term“transgenic animal” is not meant to encompass classical cross-breedingor in vitro fertilization, but rather is meant to encompass animals inwhich one or more cells are altered by or receive a recombinant DNAmolecule. This molecule may be specifically targeted to a definedgenetic locus, be randomly integrated within a chromosome, or it may beextrachromosomally replicating DNA. The term “germ cell line transgenicanimal” refers to a transgenic animal in which the genetic alteration orgenetic information was introduced into a germ line cell, therebyconferring the ability to transfer the genetic information to offspring.If such offspring, in fact, possess some or all of that alteration orgenetic information, then they, too, are transgenic animals.

The alteration of genetic information may be foreign to the species ofanimal to which the recipient belongs, or foreign only to the particularindividual recipient, or may be genetic information already possessed bythe recipient. In the last case, the altered or introduced gene may beexpressed differently than the native gene. Such altered or foreigngenetic information would encompass the introduction of neurologicaldisorder-associated CNV containing nucleotide sequences.

The DNA used for altering a target gene may be obtained by a widevariety of techniques that include, but are not limited to, isolationfrom genomic sources, preparation of cDNAs from isolated mRNA templates,direct synthesis, or a combination thereof.

A preferred type of target cell for transgene introduction is theembryonal stem cell (ES). ES cells may be obtained from pre-implantationembryos cultured in vitro (Evans et al., (1981) Nature 292:154-156;Bradley et al., (1984) Nature 309:255-258; Gossler et al., (1986) Proc.Natl. Acad. Sci. 83:9065-9069). Transgenes can be efficiently introducedinto the ES cells by standard techniques such as DNA transfection or byretrovirus-mediated transduction. The resultant transformed ES cells canthereafter be combined with blastocysts from a non-human animal. Theintroduced ES cells thereafter colonize the embryo and contribute to thegerm line of the resulting chimeric animal.

One approach to the problem of determining the contributions ofindividual genes and their expression products is to use isolatedneurological disorder-associated CNV genes as insertional cassettes toselectively inactivate a wild-type gene in totipotent ES cells (such asthose described above) and then generate transgenic mice. The use ofgene-targeted ES cells in the generation of gene-targeted transgenicmice was described, and is reviewed elsewhere (Frohman et al., (1989)Cell 56:145-147; Bradley et al., (1992) Bio/Technology 10:534-539).

Techniques are available to inactivate or alter any genetic region to amutation desired by using targeted homologous recombination to insertspecific changes into chromosomal alleles. However, in comparison withhomologous extrachromosomal recombination, which occurs at a frequencyapproaching 100%, homologous plasmid-chromosome recombination wasoriginally reported to only be detected at frequencies between 10⁻⁶ and10⁻³. Nonhomologous plasmid-chromosome interactions are more frequentoccurring at levels 10⁵-fold to 10² fold greater than comparablehomologous insertion.

To overcome this low proportion of targeted recombination in murine EScells, various strategies have been developed to detect or select rarehomologous recombinants. One approach for detecting homologousalteration events uses the polymerase chain reaction (PCR) to screenpools of transformant cells for homologous insertion, followed byscreening of individual clones. Alternatively, a positive geneticselection approach has been developed in which a marker gene isconstructed which will only be active if homologous insertion occurs,allowing these recombinants to be selected directly. One of the mostpowerful approaches developed for selecting homologous recombinants isthe positive-negative selection (PNS) method developed for genes forwhich no direct selection of the alteration exists. The PNS method ismore efficient for targeting genes which are not expressed at highlevels because the marker gene has its own promoter. Non-homologousrecombinants are selected against by using the Herpes Simplex virusthymidine kinase (HSV-TK) gene and selecting against its nonhomologousinsertion with effective herpes drugs such as gancyclovir (GANC) or(1-(2-deoxy-2-fluoro-B-D arabinofluranosyl)-5-iodou-racil, (FIAU). Bythis counter selection, the number of homologous recombinants in thesurviving transformants can be increased. Utilizing neurologicaldisorder-associated CNV containing nucleic acid as a targetedinsertional cassette provides means to detect a successful insertion asvisualized, for example, by acquisition of immunoreactivity to anantibody immunologically specific for the polypeptide encoded byneurological disorder-associated CNV nucleic acid and, therefore,facilitates screening/selection of ES cells with the desired genotype.

As used herein, a knock-in animal is one in which the endogenous murinegene, for example, has been replaced with human neurologicaldisorder-associated CNV containing gene of the invention. Such knock-inanimals provide an ideal model system for studying the development ofneurological disorder(s).

As used herein, the expression of a neurological disorder-associated CNVcontaining nucleic acid, fragment thereof, or an neurologicaldisorder-associated CNV fusion protein can be targeted in a “tissuespecific manner” or “cell type specific manner” using a vector in whichnucleic acid sequences encoding all or a portion of neurologicaldisorder-associated CNV are operably linked to regulatory sequences(e.g., promoters and/or enhancers) that direct expression of the encodedprotein in a particular tissue or cell type. Such regulatory elementsmay be used to advantage for both in vitro and in vivo applications.Promoters for directing tissue specific proteins are well known in theart and described herein.

The nucleic acid sequence encoding the neurological disorder-associatedCNV of the invention may be operably linked to a variety of differentpromoter sequences for expression in transgenic animals. Such promotersinclude, but are not limited to a prion gene promoter such as hamsterand mouse Prion promoter (MoPrP), described in U.S. Pat. No. 5,877,399and in Borchelt et al., Genet. Anal. 13(6) (1996) pages 159-163; a ratneuronal specific enolase promoter, described in U.S. Pat. Nos.5,612,486, and 5,387,742; a platelet-derived growth factor B genepromoter, described in U.S. Pat. No. 5,811,633; a brain specificdystrophin promoter, described in U.S. Pat. No. 5,849,999; a Thy-1promoter; a PGK promoter; a CMV promoter; a neuronal-specificplatelet-derived growth factor B gene promoter; and Glial fibrillaracidic protein (GFAP) promoter for the expression of transgenes in glialcells.

Methods of use for the transgenic mice of the invention are alsoprovided herein. Transgenic mice into which a nucleic acid containingthe neurological disorder-associated CNV or its encoded protein havebeen introduced are useful, for example, to develop screening methods toscreen therapeutic agents to identify those capable of modulating thedevelopment of neurological disorder(s).

Pharmaceuticals and Peptide Therapies

The elucidation of the role played by the neurological disorderassociated CNVs described herein in neuronal signaling and brainstructure facilitates the development of pharmaceutical compositionsuseful for treatment and diagnosis of neurological disorder(s). Thesecompositions may comprise, in addition to one of the above substances, apharmaceutically acceptable excipient, carrier, buffer, stabilizer orother materials well known to those skilled in the art. Such materialsshould be non-toxic and should not interfere with the efficacy of theactive ingredient. The precise nature of the carrier or other materialmay depend on the route of administration, e.g. oral, intravenous,inhalation, cutaneous or subcutaneous, nasal, intramuscular,intraperitoneal routes.

Whether it is a polypeptide, antibody, peptide, nucleic acid molecule,small molecule or other pharmaceutically useful compound according tothe present invention that is to be given to an individual,administration is preferably in a “prophylactically effective amount” ora “therapeutically effective amount” (as the case may be, althoughprophylaxis may be considered therapy), this being sufficient to showbenefit to the individual.

The following materials and methods are provided to facilitate thepractice of the present invention.

Sample Ascertainment

For initial screening we assembled three sample collections: 1) 943 ASDfamilies (4,444 unique subjects) from the Autism Genetic ResourceExchange (AGRE) collection; 2) 1,070 de-identified and unrelatedchildren of European ancestry from the Children's Hospital ofPhiladelphia (CHOP), with no evidence of neurological disorders; 3) 542unrelated neurologically normal adults and seniors of European ancestryfrom the National Institute of Neurological Disorders and Stroke (NINDS)control collection. The AGRE families include 917 multiplex families, 24simplex families and 2 families without an ASD diagnosis. For allanalyses, AGRE cases annotated with “Autism” (n=1,463), “Broad Spectrum”(n=149) or “Not Quite Autism” (n=71) were treated equally and asaffected. Samples from AGRE and NINDS were genotyped using DNA extractedfrom Epstein-Barr Virus (EBV)-transformed lymphoblastoid cell lines,while the CHOP controls were genotyped using DNA extracted from wholeblood. All AGRE and control samples included in these analyses weregenotyped on the Illumina HumanHap550 version 3 arrays, and 281 samplesgenotyped on version 1 arrays were excluded from the present analysis.Since the NINDS controls were genotyped at a different location andtime, they were used to assess the frequency of specific CNVs in anindependent cohort and to address concerns of cell line artifacts. Thisstudy was approved by the Institutional Review Board of Children'sHospital of Philadelphia. All subjects provided written informed consentfor the collection of samples and subsequent analysis.

The Autism Case-Control (ACC) cohort included 859 cases from multiplesites within the United States, all of whom were of European ancestryaffected with ASD. Of those, 703 were male and 156 were female; 828 metdiagnostic criteria for autism, and 31 met criteria for other ASDs.Subjects ranged from 2-21 years of age when the Autism DiagnosticInterview (ADI) was given. Of the case subjects, 54% were from simplexfamilies with the balance coming from multiplex families. The controlgroup used for replication included 1051 children of self-reportedCaucasian ancestry who had no history of ASDs. These controls wererecruited by CHOP nursing and medical assistant staff under thedirection of CHOP clinicians within the CHOP Health Care Network,including four primary care clinics and several group practices andoutpatient practices that included well child visits.

Detection and Annotation of Copy Number Variation

For each data set, we applied identical and stringent quality controlcriteria to remove samples with low signal quality. CNV calls weregenerated using PennCNV [20], an algorithm which employs multiplesources of information, including total signal intensity, allelicintensity ratios, SNP allele frequencies, distance between neighboringSNPs, and family information to generate calls. We excluded samplesmeeting any of the following criteria: a) standard deviation forautosomal log R ratio values (LRR_SD) higher than 0.28, b) median BAllele Frequency (BAF_median) higher than 0.55 or lower than 0.45, c)fraction of markers with BAF values between 0.2 and 0.25 or 0.75 and 0.8(BAF_drift) exceeded 0.002. We also excluded from our analysis CNVswithin IGLC1 (22q11.22), IGHG1 (14q32.33) and IGKC (2p11.2), and the Tcell receptor constant chain locus (14q11.2), as well as CNVs inchromosomes showing evidence of heterosomic aberrations (chromosomerearrangements in sub-populations of cells) in BeadStudio.

CNV calls were mapped onto genes by identifying overlap with RefSeqexons, the coordinates of which we obtained from the UCSC table browser.Deletion events overlapping with exons retrieved in this way were listedas eDels. eDups were defined as gains overlapping one or more codingexons and seen to be internal to the beginning and end of thecorresponding transcript. Gains observed to encompass all exons for agiven gene were annotated as gDups. P values for relative CNV burden incases and controls were calculated at each locus by Fisher's exact test.To compare our CNV calls with other publications that have used AGREfamilies [10], [11], [21], [22], we examined published calls on the sameindividuals with the same AGRE identifiers. The CNV calls were retrievedfrom each corresponding publication. Quantitative PCR for CNVvalidationTaqMan primer/probe sets were designed to query random CNVsusing FileBuilder 3.0 on the repeat-masked human genome (NCBI_36; March2006 release; http://genome.ucsc.edu/). For each assay, 10 ng of genomicDNA was assayed in quadruplicate in 10-μL reactions containing 1×finalconcentration TaqMan Universal Master Mix (ABI part number 4304437), and200 nM of each primer and probe. Cycling was performed under defaultconditions in 384-well optical PCR plates on an ABI 7900 machine. Copynumber was defined as 2-ΔΔCT, where ΔCT is the difference in thresholdcycles for the sample in question normalized against an endogenousreference (RNAseP) and expressed relative to the average values obtainedby three arbitrary control DNAs. A list of TaqMan probes against the 12CNVs tested is included in Table 5.

Phylogenetic Analysis

Phylogenetic trees were estimated using the neighbor-joining algorithm,as implemented in PAUP 4.0, on an additive encoding of autosomalgenotypes from one randomly selected child from 912 families.

Example I Genome-Wide Analyses of Exonic Copy Number Variants in aFamily-Based Study Point to Novel Autism Susceptibility Genes

The Autism spectrum disorders (ASDs, MIM: 209850) are a heterogeneousgroup of childhood diseases characterized by abnormalities in socialbehavior and communication, as well as patterns of restricted andrepetitive behaviors[1]. Twin studies have demonstrated much higherconcordance rates of ASD in monozygotic twins (92%) than dizygotic twins(10%) [2,3] indicating a strong genetic basis for autism susceptibility.Although previous work has implicated numerous genomic regions ofinterest [4-8], the identification of specific genetic variants thatcontribute to ASD risk remains challenging.

Substantial progress towards the identification of genetic risk variantshas come from recent characterization of structural variation (i.e.,copy number variation or CNV). For example, an initial report involvingpatients with syndromic autism characterized genomic variation usingarray comparative genomic hybridization (CGH) and identified large denovo CNVs in 28% of cases [9]. Similarly, subsequent work demonstratedthat the frequency of de novo CNVs is higher in cases versus controls[7], [8]. CNV analyses have proven useful in the identification ofregions that are potentially disease-related [8], [10]-[13] and havebegun to be employed to advance the candidacy of individual genes,including NRXN1, CNTNAP2, and NHE9 [6], [14]-[16]. Recent workcharacterizing structural variation in cases and ethnically matchedcontrols associating ubiquitin-pathway genes with autism withreplicating this finding in the AGRE dataset is likewise notable [17],although family data was not reported here. Using the AGRE dataset as adiscovery cohort, along with family information available for AGREsamples, we describe distinct and complementary analyses, prioritizingexonic events over CNVs in introns and intergenic intervals, whichprovide important new insights into the genetic architecture of theASDs.

Towards the identification of additional genes and regions that maymodulate disease risk, we have assembled a resource characterizinggenome-wide structural variation from over nine hundred multiplex ASDfamilies. Presented below are results from analyses contrasting eventsobserved in cases and healthy ethnically matched controls, focusing onthree classes of genic events: exonic deletions (eDels), exonicduplications (eDups), and whole gene duplication (gDups). Recovery ofknown ASD loci—together with the identification of novel regionsharboring variants in multiple cases but no controls—supports theutility of this dataset. Consistent with enormous inter-individualvariation, we further document a large number of events observed in onlyindividual cases (Table 1). Importantly, all of these data have beenmade available to the scientific community pre-publication (on the worldwide web at agre.org), greatly enhancing the utility of existingpublicly accessible biomaterials and phenotype data. These data furtherhighlight the extent of structural variation in both human and the ASDsand offer an important resource for hypothesis-generation andinterrogation of individual loci.

To characterize structural variation in ASD multiplex families andunrelated controls, we typed individuals at 561,466 SNP markers usingIllumina HumanHap550 version 3 arrays. After excluding samples thatfailed to meet QC thresholds (see Table 2), we obtained array data on3832 individuals from 912 multiplex families enrolled in the AutismGenetic Resource Exchange (AGRE) [18], 1070 disease-free children fromthe Children's Hospital of Philadelphia (CHOP), and 418 neurologicallynormal adults and seniors from the National Institute of NeurologicalDisorders and Stroke (NINDS) control collection [19]. Using the PennCNVsoftware [20], we detected CNVs with a mean size of 59.9 Kb and meanfrequency of 24.3 events per individual (see Table 3). Sensitivitycompares favorably with previous BAC array-based [9], [21] and SNP-basedmethods [8], in which mean resolution was observed to be in the range ofMbs and hundreds of Kbs, respectively.

As a first step towards validation of genotyping accuracy we examinedthe inheritance of CNVs in the AGRE cohort. Consistent with highquality, 96.2% of CNV calls made in children were also detected in aparent. To explore the issue of genotyping accuracy further, wegenerated CNV calls for an independently generated data set in which anoverlapping set of 2,518 AGRE samples were genotyped using theAffymetrix 5.0 platform [11]. For CNVs (>500 kb) in known ASD regions(e.g. 15q11-13, 16p11.2, and 22q11.21; Table 4) [8], [11], [21], [22],we observed 100% correspondence between the two platforms forindividuals genotyped on both platforms. For further confirmation of CNVcalls, we compared de novo variants identified here to those highlightedin previous analyses of AGRE families. We identified all five de novoCNVs reported by Sebat et al [7], three of the five de novo CNVsreported by Szatmari et al [6], one de novo CNV within A2BP1 reported byMartin et al [23], and all five 16p11.2 de novo deletions reported byWeiss et al [11] and Kumar et al [10]. Of the two of thirteen de novoCNVs reported by Szatmari et al not detected as de novo in our study,one was very small (2 SNPs, 180 bp on 8p23.2), and the second clearlyappears to be inherited (469 SNPs, 1.4 Mb on 17p12). Thus, our data areconcordant with several other studies, and provide a more comprehensivepicture of de novo CNVs in multiplex autism families. To furtherevaluate the quality of these data on another independent platform, weused Taqman to determine relative copy number at 12 previouslyunreported de novo CNVs identified in AGRE probands, confirming 11/12loci (FIG. 1 and Table 5). Together these results suggest that the CNVscalls we report are consistent and reliable.

We therefore undertook additional analyses to identify specific loci inwhich structural variants were enriched in cases versus controls.Because the majority of such variants were intronic or intergenic, wesought to prioritize CNVs most likely to interfere with the molecularfunction of specific genes. We first filtered CNV calls to include onlyexonic deletions (eDels) observed to overlap with a RefSeq gene.Overall, such eDels were observed at similar frequencies in AGRE cases,1st degree relatives of AGRE cases, and unrelated controls (CHOP andNINDS cohorts), with an average of ˜2 such variants per person (Table3). To identify events related to the ASDs we then looked for genesharboring eDels in at least one case but no unrelated controls. Amongthe 284 genes that met this criteria (Table 1) we observed several knownASD or mental retardation genes including: ASPM [24], DPP10 [8], CNTNAP2[25], [26], PCDH9 [16], and NRXN1 [6]. To enrich for genes most likelyto contribute to ASD risk, we used family-based calling to evaluatewhich of these genes carried eDels in three or more cases from at leasttwo unrelated families (Table 6). This stringent filtering resulted in72 genes at 55 loci, including NRXN1. This is notable, given that elevendistinct disease-linked NRXN1 variants have been identified [6], [8],[15], [27], [28]. Neurexin family members are known to interactfunctionally with ASD-related neuroligins [29]-[32], and likewise playan important role in synaptic specification and specialization [33],[34]. eDels in more recently identified candidates, including DPP10 andPCDH9, were likewise retained. Similarly, recovery of RNF133 and RNF148within intron 2 of CADPS2 [7], [35] highlights additional complexity atthis locus. Although CNV breakpoints cannot be mapped precisely usingSNP data alone, it is possible to determine overlap with protein codingexons and use these data to predict impact on gene function. Consistentwith perturbation of function, distinct alleles at the loci highlightedhere are predicted to eliminate or truncate the corresponding proteinproducts (FIG. 2).

Importantly, CNVs at a majority of these eDel loci show uniquebreakpoints in different families and/or result in the loss of distinctexons, demonstrating that they are independent. Moreover, because it iswell established that CNVs at a subset of loci show identicalbreakpoints in unrelated individuals [10], this result is likely tounderestimate the extent to which variants described here aroseindependently. Results from multi-dimensional scaling are likewiseconsistent with the interpretation that variants we highlight aroseindependently (FIG. 3).

Given the large number of variants identified, it was criticallyimportant to confirm in an independent case-control analysis, how manyof these eDels were truly overrepresented in cases, as opposed to beingpotentially attributable to Type I error. To address this concern, wesought to determine eDel frequency in these same genes in a replicationdataset comprising 859 independently ascertained ASD cases and 1051unrelated control subjects from the Autism Case Control cohort (ACC).One third of the loci identified in the discovery phase were observed inone or more ACC controls (18/55; 32.7%), suggesting that while rare,eDels at these loci are not limited to ASD cases and family members. Incontrast, and providing evidence for formal replication, 14 separateloci encompassing 22 genes were observed to carry eDels in both AGRE andACC cases, but none of 2539 controls (Table 3). Our replication datalend strong support to the involvement of specific loci in the ASDs(Table 6). However, to ensure that these results were not observed bychance alone, we performed 10,000 permutation trials on data from thereplication cohort by permuting case/control status across individuals.In each permuted dataset, we maintained the same numbers of cases andcontrols as in the original data, and calculated the number of genesharboring CNVs exclusively in cases. None of the 10,000 permutationtrials gave results comparable to experimental observations forreplicated case-specific loci (n=14; p<0.0001; FIG. 4A). In contrast,findings comparable to those for non-replicated loci (highlighted ascase-specific in the discovery phase but subsequently seen inreplication controls) were seen in controls in 246/10,000 trials (n=18;p=0.02; FIG. 4B).

Despite the challenges associated with obtaining statistical support forindividually rare events [7], [36] we next sought to assign P values forreplicated eDel loci. We were able to obtain support for each of thefollowing loci: BZRAP1 at 17q22 (p=8.0×10⁻⁴), NRXN1 at 2p16.3(p=3.3×10⁻⁴), MDGA2 at 14q21.3 (p=1.3×10⁻⁴), MADCAM1 at 19q13(p=5.5×10⁻⁵), and a three gene locus at 15q11 (p=1.3×10⁻¹¹). CNV callsat each of 15q11 and 19p13 are highly-error prone, suggesting thatresults here be interpreted with caution Recovery of NRXN1, however,provides confidence for involvement of additional loci that werelikewise replicated. Benzodiazapine receptor (peripheral) associatedprotein 1 (BZRAP1, alternatively referred to as RIMBP1), is an adaptormolecule thought to regulate synaptic transmission by linking vesicularrelease machinery to voltage gated Ca2+ channels [37]. Identification ofthis synaptic component here, in a hypothesis-free manner, isparticularly satisfying and also provides additional support forsynaptic dysfunction in the ASDs [29], [38]. Less is known about MDGA2[39], although comparison of the predicted protein to all others withinGenBank by BLASTP indicated an unexpectedly high similarity to Contactin4 (24% identity over more than 500 amino acids; Expect=3×10-39). Givenprevious reports of hemizygous loss of CNTN4 in individuals with mentalretardation [40] and autism [17], [41]. similarity between MDGA2 andCNTN4, surpassed only by resemblance to MDGA1, is notable. Likewiseintriguing in light of the suggestion that common variation in celladhesion molecules may contribute to autism risk [42] is the structurallikeness of MDGA2 to members of this family of molecules. Similarresults were observed for three additional genes including the ChlorideChannel, Kidney, A (CLCNKA), the Kainate-Preferring Glutamate ReceptorSubunit KA2 (GRIK5), and Guanine Monophosphate synthetase (GMPS) (FIG.2); for each, eDels were identified in multiple unrelated cases, but notin any unaffected siblings or 1489 unrelated CHOP/NINDS controls (FIG.2). Moreover, for each of these genes, at least one CNV was observed toeliminate the entire protein coding sequence. Similarly, and alsoconsistent with perturbation of function, separate alleles identified inunrelated individuals are predicted to result in dramatically truncatedproteins.

Although some published analyses emphasize the greater contribution ofgene deletion events in autism pathogenesis [7], there are also clearexamples of duplications that strongly modulate ASD risk [43], [44]. Wetherefore conducted a parallel analysis of duplications, distinguishingbetween events involving entire genes (gDups) which might increasedosage and those restricted to internal exons (eDups) which could giverise to a frameshift or map to a chromosomal region distinct from thereference gene. For gDups, we identified 449 genes that were duplicatedin at least one AGRE case but no CHOP/NINDS controls (Table 1). Ofthose, 200 genes at an estimated 63 loci, including genes at 15q11.2[43], met the more stringent criteria of being present in three or morecases from at least two independent families (Table 6). Of these, 11.5%(23/200) were also seen in ACC controls, whereas 24.5% (49/200) werecase-specific in the replication cohort. Strong statistical support wasobtained for established loci (e.g. p=9.3×10⁻⁶ for UBE3A and other genesin the PWS/AS region at 15q11-q13), and nominal evidence was observedfor the following novel loci: CD8A at 2p11.2 (p=0.069), LOC285498 at4p16.3 (p=0.028), and CARD9/LOC728489 at 9q34.3 (p=0.005).

For eDups, we reasoned that duplication of one or more internal exonscould serve to disrupt the corresponding open reading frame and bepredicted to impair gene function as a result. Despite the caveat thatobserved copy number gains need not map to the wild-type locus, knownASD genes including TSC2 [45] and RAH [44], [46] within thePotocki-Lupski Syndrome critical interval were amongst the 159 lociobserved in at least one AGRE case, but no CHOP/NINDS controls (Table1). Such events were also seen in one family at the NLGN1 locus, whichis of interest given previous support for NLGN3 and NLGN4 [29].Filtering of these results, using the more stringent criteria employedabove in consideration of eDels, limited this set of events to 76 lociobserved in at least three cases from two separate families (Table 6).Interestingly, BZRAP1, reported above to harbor eDels at significantlyhigher frequencies in AGRE and ACC cases versus controls (p=8.0×10⁻⁴),was amongst these, with eDups observed here in four unrelated AGRE cases(screening p=0.021). Eight other genes, including the voltage gatedpotassium channel subunit KCNAB2 (p=4.7×10⁻³) remained absent from ACCcontrols and were also replicated in the independent case cohort.Although eDups at BZRAP1 were not detected in ACC cases, eDels at thislocus were replicated, underscoring the importance of variation here.When considering eDels and eDups at the BZRAP1 locus together, thelikelihood of such an observation occurring by chance alone is small(p=2.3×10⁻⁵). Although none of the variants we highlight were observedin any of 2539 unrelated controls, key events, including eDels at NRXN1,BZRAP1, and MDGA2 were observed in both cases and non-autistic familymembers (FIG. 5). This is in keeping with previous work which suggeststhat haploinsufficiency at NRXN1 may contribute to the ASDs [15], but isinsufficient to cause disease. Such data are also consistent with thewell established finding of the “broader autism phenotype”, such assubclinical language and social impairment in first degree relatives ofcases with an ASD, which supports a multilocus model [47], [48]. We werealso surprised to see that key variants at these loci appear to betransmitted to only a subset of affected individuals in some families(FIG. 5). These observations parallel findings at other major effectloci including 16p11.2 [11] and DISCI [49], [50] and are consistent witha model in which multiple variants, common and rare, act in concert toshape clinical presentation [51]-[53]. Results are also consistent withthe idea that true risk loci are likely to show incomplete penetranceand imperfect segregation with disease [13], a reality that willcomplicate gene finding efforts. Related to this is that substantialeffort will be required to determine whether rare alleles of moderateeffect act independently on distinct aspects of disease (endophenotypemodel) or together to undermine key processes in brain development(threshold model).

By limiting CNV calls to include only exonic deletions (eDels) andduplications (eDups and gDups), we have attempted to enrich for variantsmost likely to impact gene function and in doing so improve the signalto noise ratio similar to work in other complex diseases [55]. At thesame time, like other gene-based strategies, we preserve our ability toconsider eDels involving the same transcriptional unit as separate butequivalent. Given that such events appear rare, this is an importantconsideration.

Pathway analysis by DAVID [56] found support for overrepresentation ofcell adhesion molecules amongst recurrent eDel genes (uncorrectedp=0.002; CDH17, PCDH9, LAMA2, MADCAM1, NRXN1, POSTN, SPON2), although itshould be noted that this analysis does not adjust for gene size and mayfavor larger genes. Nevertheless, aside from SPON2 no eDels in thesegenes were observed in any of the controls interrogated. In contrast, noevidence for such overrepresentation was observed for genes in theubiquitin degradation pathway and neither term was highlighted asoverrepresented amongst eDups or gDups. Given that this study focusedonly on events encompassing RefSeq exons, differences from Glessner andcolleagues [17] are to be expected.

In summary, we have performed a high resolution genome-wide analysis tocharacterize the genomic landscape of copy number variation in ASDs.Through comparison of structural variation in 1,771 ASD cases and 2,539controls and prioritization of events encompassing exons we identifiedmore than 150 loci harboring rare variants in multiple probands but nocontrol individuals. For each class of structural variant interrogated,the recovery of known loci serves to validate the methods employed andresults obtained. Greatest confidence should be placed in loci harboringvariants in multiple unrelated cases but no controls and also recoveredin both screening and replication cohorts. Amongst novel genes, bestsupport was obtained for BZRAP1 and MDGA2, intriguing candidate geneswhich provide novel targets for the development of therapeutics usefulfor the treatment of ASDs.

Example II Screening Assays for Identifying Efficacious Therapeutics forthe Treatment of Autism and ASD

The information herein above can be applied clinically to patients fordiagnosing an increased susceptibility for developing autism or autismspectrum disorder and therapeutic intervention. A preferred embodimentof the invention comprises clinical application of the informationdescribed herein to a patient. Diagnostic compositions, includingmicroarrays, and methods can be designed to identify the geneticalterations described herein in nucleic acids from a patient to assesssusceptibility for developing autism or ASD. This can occur after apatient arrives in the clinic; the patient has blood drawn, and usingthe diagnostic methods described herein, a clinician can detect a CNV asdescribed in Example I. The information obtained from the patientsample, which can optionally be amplified prior to assessment, will beused to diagnose a patient with an increased or decreased susceptibilityfor developing autism or ASD. Kits for performing the diagnostic methodof the invention are also provided herein. Such kits comprise amicroarray comprising at least one of the SNPs provided herein in andthe necessary reagents for assessing the patient samples as describedabove.

The identity of autism/ASD involved genes and the patient results willindicate which variants are present, and will identify those thatpossess an altered risk for developing ASD. The information providedherein allows for therapeutic intervention at earlier times in diseaseprogression than previously possible. Also as described herein above,BZRAP1, and MDGA2 provide a novel targets for the development of newtherapeutic agents efficacious for the treatment of this neurologicaldisease.

REFERENCES

-   1. Abrahams B S, Geschwind D H (2008) Advances in autism genetics:    on the threshold of a new neurobiology. Nat Rev Genet 9: 341-355.-   2. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, et    al. (1995) Autism as a strongly genetic disorder: evidence from a    British twin study. Psychol Med 25: 63-77.-   3. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg I C,    et al. (1989) A twin study of autism in Denmark, Finland, Iceland,    Norway and Sweden. J Child Psychol Psychiatry 30: 405-416.-   4. Cantor R M, Kono N, Duvall J A, Alvarez-Retuerto A, Stone J L, et    al. (2005) Replication of autism linkage: fine-mapping peak at    17q21. Am J Hum Genet 76: 1050-1056.-   5. Vorstman J A, Staal W G, van Daalen E, van Engeland H,    Hochstenbach P F, et al. (2006) Identification of novel autism    candidate regions through analysis of reported cytogenetic    abnormalities associated with autism. Mol Psychiatry 11: 118-28.-   6. Szatmari P, Paterson A D, Zwaigenbaum L, Roberts W, Brian J, et    al. (2007) Mapping autism risk loci using genetic linkage and    chromosomal rearrangements. Nat Genet 39: 319-328.-   7. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, et    al. (2007) Strong association of de novo copy number mutations with    autism. Science 316: 445-449.-   8. Marshall C R, Noor A, Vincent J B, Lionel A C, Feuk L, et    al. (2008) Structural variation of chromosomes in autism spectrum    disorder. Am J Hum Genet 82:477-488.-   9. Jacquemont M L, Sanlaville D, Redon R, Raoul O, Cormier-Daire V,    et al. (2006) Array-based comparative genomic hybridisation    identifies high frequency of cryptic chromosomal rearrangements in    patients with syndromic autism spectrum disorders. J Med Genet 43:    843-849.-   10. Kumar R A, Karamohamed S, Sudi J, Conrad D F, Brune C, et    al. (2007) Recurrent 16p11.2 microdeletions in autism. Hum Mol    Genet.-   11. Weiss L A, Shen Y, Korn J M, Arking D E, Miller D T, et    al. (2008) Association between Microdeletion and Microduplication at    16p11.2 and Autism. N Engl J Med.-   12. Sharp A J, Mefford H C, Li K, Baker C, Skinner C, et al. (2008)    A recurrent 15q13.3 microdeletion syndrome associated with mental    retardation and seizures. Nat Genet 40: 322-328.-   13. Mefford H C, Sharp A J, Baker C, Itsara A, Jiang Z, et    al. (2008) Recurrent rearrangements of chromosome 1q21.1 and    variable pediatric phenotypes. N Engl J Med 359: 1685-1699.-   14. Alarcon M, Abrahams B S, Stone J L, Duvall J A, Perederiy J V,    et al. (2008) Linkage, Association, and Gene-Expression Analyses    Identify CNTNAP2 as an Autism-Susceptibility Gene. Am J Hum Genet    82: 150-159.-   15. Kim H G, Kishikawa S, Higgins A W, Seong I S, Donovan D J, et    al. (2008) Disruption of neurexin 1 associated with autism spectrum    disorder. Am J Hum Genet 82: 199-207.-   16. Morrow E M, Yoo S Y, Flavell S W, Kim T K, Lin Y, et al. (2008)    Identifying autism loci and genes by tracing recent shared ancestry.    Science 321: 218-223.-   17. Glessner J T, Wang K, Cai G, Korvatska O, Kim C E, et al. (2009)    Autism genome-wide copy number variation reveals ubiquitin and    neuronal genes. Nature.-   18. Geschwind D H, Sowinski J, Lord C, Iversen P, Shestack J, et    al. (2001) The autism genetic resource exchange: a resource for the    study of autism and related neuropsychiatric conditions. Am J Hum    Genet 69: 463-466.-   19. Nalls M A, Simon-Sanchez J, Gibbs J R, Paisan-Ruiz C, Bras J T,    et al. (2009) Measures of autozygosity in decline: globalization,    urbanization, and its implications for medical genetics. PLoS Genet    5: e1000415. doi:10.1371/journal.pgen.1000415.-   20. Wang K, Li M, Hadley D, Liu R, Glessner J, et al. (2007)    PennCNV: an integrated hidden Markov model designed for    high-resolution copy number variation detection in whole-genome SNP    genotyping data. Genome Res 17: 1665-1674.-   21. Christian S L, Brune C W, Sudi J, Kumar R A, Liu S, et    al. (2008) Novel submicroscopic chromosomal abnormalities detected    in autism spectrum disorder. Biol Psychiatry 63: 1111-1117.-   22. Cai G, Edelmann L, Goldsmith J E, Cohen N, Nakamine A, et    al. (2008) Multiplex ligation-dependent probe amplification for    genetic screening in autism spectrum disorders: Efficient    identification of known microduplications and identification of a    novel microduplication in ASMT. BMC Med Genomics 1: 50.-   23. Martin C L, Duvall J A, Ilkin Y, Simon J S, Arreaza M G, et    al. (2007) Cytogenetic and molecular characterization of A2BP1/FOX1    as a candidate gene for autism. Am J Med Genet B Neuropsychiatr    Genet 144: 869-876.-   24. Bond J, Roberts E, Mochida G H, Hampshire D J, Scott S, et    al. (2002) ASPM is a major determinant of cerebral cortical size.    Nat Genet 32: 316-320.-   25. Bakkaloglu B, O'Roak B J, Louvi A, Gupta A R, Abelson J F, et    al. (2008) Molecular Cytogenetic Analysis and Resequencing of    Contactin Associated Protein-Like 2 in Autism Spectrum Disorders. Am    J Hum Genet 82: 165-173.-   26. Strauss K A, Puffenberger E G, Huentelman M J, Gottlieb S,    Dobrin S E, et al. (2006) Recessive symptomatic focal epilepsy and    mutant contactin-associated protein-like 2. N Engl J Med 354:    1370-1377.-   27. Feng J, Schroer R, Yan J, Song W, Yang C, et al. (2006) High    frequency of neurexin lbeta signal peptide structural variants in    patients with autism. Neurosci Lett 409: 10-13.-   28. Yan J, Noltner K, Feng J, Li W, Schroer R, et al. (2008)    Neurexin lalpha structural variants associated with autism. Neurosci    Lett 438: 368-370.-   29. Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, et    al. (2003) Mutations of the X-linked genes encoding neuroligins    NLGN3 and NLGN4 are associated with autism. Nat Genet 34: 27-29.-   30. Comoletti D, De Jaco A, Jennings L L, Flynn R E, Gaietta G, et    al. (2004) The Arg451Cys-neuroligin-3 mutation associated with    autism reveals a defect in protein processing. J Neurosci 24:    4889-4893.-   31. Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, et    al. (2004) X-linked mental retardation and autism are associated    with a mutation in the NLGN4 gene, a member of the neuroligin    family. Am J Hum Genet 74:552-557.-   32. Yan J, Oliveira G, Coutinho A, Yang C, Feng J, et al. (2005)    Analysis of the neuroligin 3 and 4 genes in autism and other    neuropsychiatric patients. Mol Psychiatry 10: 329-332.-   33. Scheiffele P, Fan J, Choih J, Fetter R, Serafini T (2000)    Neuroligin expressed in nonneuronal cells triggers presynaptic    development in contacting axons. Cell 101: 657-669.-   34. Graf E R, Zhang X, Jin S X, Linhoff M W, Craig A M (2004)    Neurexins induce differentiation of GABA and glutamate postsynaptic    specializations via neuroligins. Cell 119: 1013-1026.-   35. Sadakata T, Washida M, Iwayama Y, Shoji S, Sato Y, et al. (2007)    Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2    splicing in autistic patients. J Clin Invest 117: 931-943.-   36. Walsh T, McClellan J M, McCarthy S E, Addington A M, Pierce S B,    et al. (2008) Rare structural variants disrupt multiple genes in    neurodevelopmental pathways in schizophrenia. Science 320: 539-543.-   37. Wang Y, Sugita S, Sudhof T C (2000) The RIM/NIM family of    neuronal C2 domain proteins. Interactions with Rab3 and a new class    of Src homology 3 domain proteins. J Biol Chem 275: 20033-20044.-   38. Zoghbi H Y (2003) Postnatal neurodevelopmental disorders:    meeting at the synapse? Science 302: 826-830.-   39. Litwack E D, Babey R, Buser R, Gesemann M, O'Leary D D (2004)    Identification and characterization of two novel brain-derived    immunoglobulin superfamily members with a unique structural    organization. Mol Cell Neurosci 25: 263-274.-   40. Fernandez T, Morgan T, Davis N, Klin A, Morris A, et al. (2004)    Disruption of contactin 4 (CNTN4) results in developmental delay and    other features of 3p deletion syndrome. Am J Hum Genet 74:    1286-1293.-   41. Roohi J, Montagna C, Tegay D H, Palmer L E, DeVincent C, et    al. (2009) Disruption of contactin 4 in three subjects with autism    spectrum disorder. J Med Genet 46: 176-182.-   42. Wang K, Zhang H, Ma D, Bucan M, Glessner J T, et al. (2009)    Common genetic variants on 5p14.1 associate with autism spectrum    disorders. Nature.-   43. Cook E H Jr, Lindgren V, Leventhal B L, Courchesne R, Lincoln A,    et al. (1997) Autism or atypical autism in maternally but not    paternally derived proximal 15q duplication. Am J Hum Genet 60:    928-934.-   44. Potocki L, Bi W, Treadwell-Deering D, Carvalho C M, Eifert A, et    al. (2007) Characterization of Potocki-Lupski syndrome    (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical    interval that can convey an autism phenotype. Am J Hum Genet 80:    633-649.-   45. Identification and characterization of the tuberous sclerosis    gene on chromosome 16. Cell 75: 1305-1315.-   46. Slager R E, Newton T L, Vlangos C N, Finucane B, Elsea S    H (2003) Mutations in RAI1 associated with Smith-Magenis syndrome.    Nat Genet 33: 466-468.-   47. Bolton P, Macdonald H, Pickles A, Rios P, Goode S, et al. (1994)    A case-control family history study of autism. J Child Psychol    Psychiatry 35: 877-900.-   48. Bishop D V, Maybery M, Maley A, Wong D, Hill W, et al. (2004)    Using selfreport to identify the broad phenotype in parents of    children with autistic spectrum disorders: a study using the    Autism-Spectrum Quotient. J Child Psychol Psychiatry 45: 1431-1436.-   49. Millar J K, Wilson-Annan J C, Anderson S, Christie S, Taylor M    S, et al. (2000) Disruption of two novel genes by a translocation    co-segregating with schizophrenia. Hum Mol Genet 9: 1415-1423.-   50. Sachs N A, Sawa A, Holmes S E, Ross C A, DeLisi L E, et    al. (2005) A frameshift mutation in Disrupted in Schizophrenia 1 in    an American family with schizophrenia and schizoaffective disorder.    Mol Psychiatry 10: 758-764.-   51. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, et al. (1999)    A genomic screen of autism: evidence for a multilocus etiology. Am J    Hum Genet 65: 493-507.-   52. Rzhetsky A, Wajngurt D, Park N, Zheng T (2007) Probing genetic    overlap among complex human phenotypes. Proc Natl Acad Sci USA    104:11694-11699.-   53. Bodmer W, Bonilla C (2008) Common and rare variants in    multifactorial susceptibility to common diseases. Nat Genet 40:    695-701.-   54. Yang S, Wang K, Gregory B, Berrettini W, Wang L S, et al. (2009)    Genomic landscape of a three-generation pedigree segregating    affective disorder. PLoS ONE 4: e4474.    doi:10.1371/journal.pone.0004474.-   55. Ji W, Foo J N, O'Roak B J, Zhao H, Larson M G, et al. (2008)    Rare independent mutations in renal salt handling genes contribute    to blood pressure variation. Nat Genet 40: 592-599.-   56. Dennis G Jr, Sherman B T, Hosack D A, Yang J, Gao W, et    al. (2003) DAVID: Database for Annotation, Visualization, and    Integrated Discovery. Genome Biol 4: P3.

TABLE 1 AGRE. AGRE. Cases. Screening. ACC. ACC. Cases. gene classUnrelated Controls Cases Controls Total RE.Family.ID ABCB9 gdups 3 0 0 05 AU1378, AU1289, AU0899, AU0836, AU0688, AU0001 ABCC1 edups 3 0 0 0 4AU1326, AU0301, AU1534 ABHD8 gdups 2 0 0 0 2 AU2005, AU1963, AU0806ACAT1 gdups 1 0 0 0 2 AU0022 ACP1 edels 1 0 0 0 2 AU0385 ACP6 gdups 3 03 0 4 AU1688, AU1610, AU1163 ACTRT1 gdups 1 0 0 0 2 AU1764 ACYP2 edels 20 0 1 2 AU0930, AU0381 ADAM10 gdups 1 0 0 0 2 AU0467 ADAM22 edels 1 0 00 2 AU1221 ADAMTS5 gdups 2 0 0 0 3 AU1416, AU1227, AU0753, AU0158ADAMTS8 edels 2 0 0 0 2 AU0939, AU0821 ADAMTSL1 edups 2 0 0 0 3 AU1496,AU0899, AU1594 ADAMTSL2 gdups 2 0 0 0 2 AU1273, AU0897, AU0520, AU1650,AU0806 ADCK1 gdups 1 0 0 0 2 AU0755 ADCY1 edups 3 0 0 0 3 AU1486,AU1331, AU1047, AU0828, AU0196, AU0168, AU0012 ADCYAP1 gdups 1 0 0 0 2AU0827 ADM2 gdups 4 0 0 0 4 AU1764, AU1212, AU1174, AU1164, AU0974,AU0899, AU0616, AU1944, AU1216 ADPRHL1 edels 1 0 0 0 2 AU1327 AFMIDgdups 2 0 0 0 2 AU1174, AU0947, AU0991, AU0835 AGL edups 2 0 0 0 2AU1833, AU0799, AU0771, AU0411 AHCTF1 edups 1 0 0 0 2 AU1668 AHR gdups 20 0 1 3 AU0440, AU0386 AK7 edels 1 0 0 0 2 AU0934 AKR1B10 edels 2 0 0 02 AU1145, AU0714 AKT1S1 gdups 2 0 1 0 2 AU1273, AU1072, AU0880, AU0698,AU0520, AU0068 ALDH3B2 gdups 1 0 0 0 3 AU1414, AU1228 ALKBH1 gdups 1 0 00 2 AU0755 ALPK3 edels 1 0 0 0 3 AU0561 AMBP gdups 1 0 0 0 2 AU0227ANGPTL4 gdups 2 0 0 0 2 AU1592, AU1209, AU1189, AU1174, AU0899, AU0806ANKRD41 gdups 2 0 0 0 2 AU2005, AU1963, AU0806 ANTXR2 edels 2 0 0 11 2AU0753, AU0388, AU0114 APBA3 gdups 3 0 0 0 3 AU0520, AU0991, AU0866,AU0806 APLP1 gdups 3 0 0 0 4 AU1136, AU0599, AU0507 APOBEC3C gdups 1 0 00 2 AU1072, AU0550 APOBEC3D gdups 1 0 0 0 2 AU1072, AU0550 APOBEC3Fgdups 1 0 0 1 2 AU1535, AU1072, AU0932, AU0550 ARHGEF16 edups 3 0 0 0 5AU1830, AU1465, AU1412, AU1078 ARHGEF4 edels 2 0 0 0 2 AU1612, AU0991ARID3A edups 4 0 0 0 7 AU0772, AU0725, AU0565, AU0308, AU0301, AU0139ARIH1 edels 1 0 0 1 2 AU1309 ARL11 gdups 4 0 0 0 5 AU1056, AU0689,AU0325, AU0168, AU0055 ARRB1 edups 2 0 0 1 2 AU0430, AU0025, AU0556ARRDC5 gdups 2 0 0 0 2 AU1912, AU1742, AU1728, AU1273, AU1193, AU1190,AU1174, AU0007, AU1527, AU0481 ARSA gdups 4 0 0 1 5 AU0794, AU0772,AU0616, AU0145, AU0051 ARSD edels 2 0 0 0 3 AU1212, AU0338 ARSD gdups 20 0 0 3 AU1212, AU0338, AU1625, AU0361 ARVCF gdups 4 0 4 0 4 AU1189,AU1174, AU0018, AU0991, AU0688, AU0049 ASCC3 edups 3 0 0 0 3 AU0489,AU1533, AU0982, AU0301 ASPM edels 2 0 0 1 2 AU0662, AU0176, AU0102 ATCAYgdups 3 0 0 0 3 AU0520, AU0991, AU0866, AU0806 ATP10A gdups 6 0 7 0 8AU1331, AU0106, AU0065, AU1135, AU0385, AU0233 ATP11C edels 1 0 0 0 2AU1823 ATP6V0D1 edups 1 0 0 0 2 AU1482, AU0700 ATP6V0D1 gdups 3 0 0 0 3AU1207, AU0962, AU1368, AU0991, AU0835 AXUD1 gdups 1 0 0 0 2 AU1424 BAG2edels 1 0 0 0 2 AU1215 BAI1 edups 2 0 0 0 2 AU0616, AU0568 BAIAP3 edups1 0 0 0 2 AU1172 BBS2 gdups 1 0 0 0 2 AU1197 BC002942 gdups 5 0 0 0 6AU1912, AU1764, AU1212, AU1174, AU1164, AU1158, AU0899, AU0616, AU1944,AU1216, AU0806 BCL9 gdups 3 0 3 0 4 AU1688, AU1610, AU1163 BCMO1 gdups 10 0 1 2 AU1019, AU0708 BDH1 gdups 1 0 0 0 2 AU1407, AU1087, AU0477 BGNgdups 2 0 0 0 2 AU0947, AU0897, AU0562, AU0122, AU0866 BIRC5 gdups 2 0 01 2 AU1174, AU0947, AU0991, AU0835 BIRC7 edups 2 0 0 0 2 AU0106, AU1915BLOC1S2 edels 1 0 0 0 2 AU1016 BMP2K edups 1 0 0 0 2 AU1698 BNIP2 gdups1 0 0 0 2 AU0467 BTBD2 edels 1 0 0 1 2 AU1806, AU1753 BTBD4 edups 3 0 00 6 AU1397, AU1273, AU0920, AU0307, AU0215 BTBD4 gdups 2 0 0 0 2 AU0939,AU0934, AU0543, AU0109 BTN2A1 edels 2 0 0 1 4 AU0561, AU0215 BTN2A3edels 1 0 0 1 3 AU0561 BTN3A3 edels 1 0 0 1 3 AU0561 BXDC1 edels 1 0 0 14 AU0001 BXDC1 edups 2 0 0 0 3 AU1423, AU1341 BZRAP1 edels 6 0 2 0 8AU1921, AU1286, AU1171, AU1105, AU0948, AU0897, AU0831, AU0803 BZRAP1edups 4 0 0 0 4 AU1813, AU1341, AU1226, AU0899, AU0880, AU0616, AU0540,AU0085 C10orf49 edels 1 0 0 0 2 AU0305 C10orf53 gdups 2 0 0 0 2 AU0845,AU0329 C10orf72 edups 9 0 0 1 12 AU1282, AU1078, AU0994, AU0971, AU0952,AU0802, AU0698, AU0696, AU0616, AU0277, AU0134, AU0063, AU1691, AU1065C11orf72 gdups 3 0 0 0 5 AU1414, AU1228, AU1527, AU0806 C12orf38 gdups 20 0 0 3 AU1007, AU0346, AU0152 C12orf49 edels 1 0 0 0 2 AU1228 C14orf151edups 2 0 0 0 2 AU0084, AU1315 C14orf156 gdups 1 0 0 0 2 AU0755C14orf173 edups 2 0 0 0 2 AU0084, AU1315 C15orf2 gdups 6 0 8 0 10AU1875, AU1331, AU0744, AU0106, AU0065, AU1135, AU0233 C16orf30 gdups 20 0 0 2 AU0932, AU0616, AU0008, AU0688 C17orf58 gdups 1 0 0 0 2 AU1685C19orf10 gdups 2 0 0 0 2 AU1164, AU1099, AU0947, AU0616, AU0866 C19orf15edels 1 0 0 0 2 AU1685 C19orf19 edels 3 0 7 0 3 AU1286, AU1102, AU0995,AU1301, AU0194 C19orf20 edels 2 0 7 0 2 AU1286, AU1301, AU0194 C19orf21edups 1 0 0 0 2 AU0022 C1GALT1 edels 1 0 0 0 2 AU0487 C1orf101 edels 1 00 0 2 AU0955 C1orf171 gdups 1 0 0 0 2 AU1285, AU0110 C1orf192 gdups 2 00 0 2 AU1875, AU1614 C1orf93 gdups 4 0 0 0 4 AU0934, AU0899, AU0880,AU0841, AU0816, AU0693, AU0520, AU0161, AU1409, AU0866, AU0481 C1QTNF1edels 8 0 0 6 11 AU1779, AU1650, AU1338, AU1301, AU1292, AU1286, AU0951,AU0932, AU0598, AU1332, AU1107, AU0903, AU0803 C20orf141 gdups 2 0 0 0 2AU1391, AU0758, AU0752, AU0509, AU0111, AU0049, AU0790 C20orf151 edels 20 0 20 2 AU1231, AU1318, AU0803 C20orf72 gdups 1 0 0 0 2 AU1520 C21orf34edups 1 0 0 0 2 AU0799 C21orf51 gdups 3 0 0 2 4 AU1510, AU1233, AU1227,AU1213, AU0753, AU0747, AU0661, AU1213, AU0158 C21orf70 gdups 2 0 0 0 2AU1227, AU1039, AU0753, AU0158 C22orf25 gdups 3 0 4 0 3 AU0520, AU0018,AU0991, AU0049 C22orf29 gdups 3 0 4 0 3 AU0018, AU0991, AU0049 C6orf107gdups 2 0 0 1 2 AU1575, AU1412, AU0668 C6orf213 edels 1 0 0 0 2 AU0880C6orf65 edels 1 0 0 0 3 AU1533 C7orf20 gdups 1 0 0 0 2 AU0385 C7orf27gdups 2 0 0 0 2 AU0555, AU0806 C8orf74 edels 1 0 0 0 2 AU1171 C9orf28edups 2 0 0 0 4 AU1255, AU0780, AU0352 C9orf48 edels 1 0 0 1 2 AU0535C9orf7 gdups 2 0 0 0 2 AU1273, AU0897, AU0520, AU1650, AU0806 C9orf90gdups 2 0 0 0 2 AU1174, AU0866, AU0835 CA5A edups 3 0 0 0 3 AU0565,AU0308, AU0820 CA6 edels 3 0 1 0 3 AU1907, AU1226, AU0314 CABLES2 edels2 0 0 19 2 AU1231, AU1318, AU0803 CACHD1 edups 3 0 0 0 5 AU0285, AU0029,AU1224 CACNA2D2 edups 1 0 0 0 2 AU1189, AU0178 CACNA2D4 edups 5 0 0 0 5AU1551, AU1234, AU1072, AU0947, AU0263, AU0991 CALB2 gdups 1 0 0 0 2AU1551 CALCR edels 2 0 0 0 2 AU1212, AU0049 CAND2 edels 2 0 0 0 3AU1377, AU0025 CARD11 edups 3 0 0 1 4 AU1427, AU1328, AU1298 CARD9 gdups5 0 1 0 5 AU1197, AU1072, AU0947, AU0934, AU0897, AU1283, AU1216,AU1033, AU0991, AU0068 CASQ2 gdups 1 0 0 0 2 AU0651 CBLN3 gdups 4 0 0 05 AU0980, AU0974, AU0742, AU0568, AU0551, AU0399 CBR1 gdups 2 0 0 0 3AU1227, AU0753, AU0316, AU0158 CCDC3 edels 1 0 0 0 2 AU0305 CCDC46 edels2 0 0 1 2 AU0742, AU0452, AU0121, AU0051 CCDC65 edups 1 0 0 0 2 AU1353CCDC67 edels 1 0 0 0 2 AU1261 CCDC94 gdups 2 0 0 0 2 AU1164, AU1099,AU0947, AU0934, AU0991 CCL1 gdups 1 0 0 1 2 AU1559, AU0018 CCL11 gdups 10 0 1 2 AU1559, AU0018 CCL13 gdups 2 0 0 3 3 AU1559, AU0450, AU0018CCL14 gdups 1 0 0 0 2 AU0806 CCL15 gdups 1 0 0 0 2 AU0806 CCL18 gdups 10 0 0 2 AU0806 CCL2 gdups 1 0 0 1 2 AU1559, AU0018 CCL23 gdups 1 0 0 0 2AU0806 CCL3 edels 1 0 0 0 2 AU1551 CCL7 gdups 1 0 0 1 2 AU1559, AU0018CCL8 gdups 1 0 0 1 2 AU1559, AU0018 CCNB2 gdups 1 0 0 0 2 AU0467 CCRKedels 1 0 0 0 2 AU1516 CD8A gdups 2 0 1 0 3 AU1338, AU0600 CDC42EP4edels 1 0 0 0 2 AU1921, AU1301 CDC45L gdups 3 0 4 0 3 AU0018, AU0991,AU0049 CDC5L edups 1 0 0 0 3 AU1867 CDH17 edels 2 0 0 0 3 AU0938, AU0355CDK5RAP2 edups 1 0 0 0 2 AU0993, AU0076 CDK9 gdups 2 0 0 0 2 AU1174,AU1164, AU0932, AU0298, AU1650 CDR1 edels 1 0 0 0 2 AU1823 CDRT15 edels1 0 0 1 2 AU0149 CDRT15 gdups 1 0 0 0 2 AU0707 CDRT4 edels 1 0 0 1 2AU0149 CDRT4 gdups 1 0 0 0 2 AU0707 CEBPA gdups 3 0 0 1 3 AU1273,AU0934, AU0897, AU1963, AU1216, AU0991 CEL gdups 2 0 0 0 2 AU0698,AU0866 CELSR1 edups 6 0 0 0 7 AU1778, AU0688, AU0627, AU0540, AU0371,AU0307, AU1728, AU1527 CENPT gdups 3 0 0 0 4 AU0647, AU1368, AU1055CENTA1 gdups 1 0 0 0 2 AU0385 CERK edups 3 0 0 0 5 AU0932, AU0816,AU0467, AU1610, AU0068 CERK gdups 5 0 0 0 5 AU1963, AU1527, AU1216,AU0806, AU0481 CGB gdups 1 0 0 3 2 AU1088 CGB1 gdups 2 0 0 2 3 AU1088,AU0698 CGB2 gdups 2 0 0 2 3 AU1088, AU0698 CGB5 gdups 2 0 0 2 3 AU1088,AU0698 CGB8 gdups 2 0 0 2 3 AU1088, AU0698 CGI-38 gdups 3 0 0 0 3AU1207, AU0962, AU1368, AU0991, AU0835 CHD1L gdups 2 0 3 0 3 AU1610,AU1163, AU1688 CHD9 edups 2 0 1 0 3 AU1558, AU1511 CHIC2 edels 2 0 0 0 2AU0533, AU1333, AU0779 CHODL edels 1 0 0 0 2 AU0276 CHRNA4 edels 1 0 0 02 AU1921, AU0033 CHRNA4 gdups 2 0 0 0 2 AU1174, AU0932, AU0693, AU0678,AU0520, AU0991, AU0806 CHRNG gdups 1 0 0 0 2 AU1213, AU0520 CHST3 gdups1 0 0 0 2 AU0862 CLCN7 edups 1 0 0 0 2 AU1990, AU1806 CLCNKA edels 4 0 00 4 AU1875, AU1048, AU0106, AU1944 CLDN17 gdups 2 0 0 0 3 AU1227,AU0816, AU0753, AU0158 CLDN5 gdups 3 0 4 0 3 AU0018, AU0991, AU0049CLDN6 edels 2 0 4 0 2 AU1085, AU1338, AU1107 CLDN8 gdups 2 0 0 0 3AU1227, AU0816, AU0753, AU0158 CLDN9 edels 2 0 4 0 2 AU1085, AU1338,AU1107 CLEC2D edups 1 0 0 0 2 AU1444 CLEC4G gdups 1 0 0 0 2 AU1730CLTCL1 gdups 3 0 4 0 3 AU0018, AU0991, AU0049 CNNM1 edels 1 0 0 0 2AU0325 CNTNAP2 edels 2 0 0 0 2 AU0880, AU0193 COG4 gdups 1 0 0 0 2AU1551, AU0686 COL16A1 edups 5 0 0 1 6 AU1594, AU1158, AU0980, AU0763,AU0689, AU0258, AU0110, AU1283, AU0835 COL20A1 edels 1 0 0 3 2 AU1921,AU0033 COL20A1 edups 1 0 0 0 2 AU0325 COL20A1 gdups 2 0 0 0 2 AU1174,AU0932, AU0693, AU0678, AU0520, AU0991, AU0806 COL22A1 edups 1 0 0 0 3AU0430 COL27A1 edels 2 0 0 1 4 AU1301, AU0489 COL6A1 edups 2 0 0 0 2AU1764, AU0991 COMT gdups 3 0 4 0 3 AU0018, AU0991, AU0049 COQ7 gdups 10 0 0 2 AU0993 CORO7 gdups 4 0 0 0 5 AU1742, AU1212, AU1207, AU1174,AU1164, AU0971, AU0947, AU0899, AU0830, AU0688, AU0678, AU0081, AU1963COX10 edels 1 0 0 1 2 AU0149 COX4I1 gdups 3 0 0 0 4 AU0920, AU0298,AU0179 CPNE5 edups 2 0 0 0 2 AU0905, AU1230 CPNE7 edups 3 0 0 0 4AU1417, AU0795, AU0777, AU1921 CPS1 edels 1 0 0 0 2 AU0717 CPXM2 edups 20 0 0 2 AU1215, AU0053 CREB3L3 gdups 9 0 0 0 9 AU1099, AU0991, AU0947,AU0934, AU0911, AU0897, AU0241, AU0206, AU1527, AU0866, AU0742, AU0688,AU0676 CRELD2 gdups 3 0 0 0 3 AU1742, AU1368, AU1174, AU1055, AU0932,AU0916, AU0520, AU0991 CRYGA gdups 1 0 0 0 2 AU1060 CRYZ gdups 1 0 0 0 2AU1285, AU0110 CSAG2 gdups 1 0 0 0 2 AU1439, AU0254 CSAG3B gdups 1 0 0 02 AU1439, AU0254 CSTF2T gdups 2 0 0 0 3 AU0640, AU0329 CT45-5 gdups 2 00 0 2 AU0542, AU0080 CT45-6 gdups 2 0 0 0 2 AU0542, AU0080 CWF19L1 edels1 0 0 0 2 AU1016 CXorf40A gdups 1 0 0 0 2 AU0308 CYB5R2 gdups 1 0 0 0 2AU1309 CYBASC3 gdups 2 0 0 0 3 AU1323, AU0918 CYP2B6 edels 2 0 0 1 2AU1486, AU1317 CYP4A11 gdups 1 0 0 1 3 AU0052 CYP4A22 gdups 2 0 0 0 4AU1550, AU0052 CYP4F22 edels 3 0 0 2 4 AU1685, AU1411, AU1171, AU1157,AU1069 CYP4X1 gdups 2 0 0 0 4 AU1550, AU0052 CYP4Z1 gdups 2 0 0 0 4AU1550, AU0052 DAB1 edels 1 0 0 0 2 AU0325 DACH1 edels 8 0 0 7 10AU0265, AU0250, AU0210, AU0208, AU0203, AU0179, AU0173, AU0108, AU0102,AU0098, AU0056, AU0820, AU0134, AU0123 DACT2 gdups 1 0 0 0 2 AU1409 DAKgdups 4 0 0 0 6 AU1728, AU1323, AU1215, AU1009, AU0995, AU0918, AU0658,AU0262 DAPK3 gdups 7 0 0 0 7 AU1273, AU1193, AU1189, AU1164, AU1137,AU1072, AU0947, AU0932, AU0520, AU1216, AU0991, AU0866, AU0806, AU0688DAZAP1 gdups 8 0 0 0 8 AU1778, AU1632, AU1368, AU1353, AU1277, AU1212,AU1207, AU1174, AU1164, AU0974, AU0939, AU0934, AU0924, AU0899, AU0883,AU0795, AU0753, AU0081, AU1944, AU1527, AU1033, AU0866, AU0835 DBH edups2 0 0 0 3 AU1695, AU1536, AU1289 DCUN1D2 edels 1 0 0 0 2 AU1327 DDB1gdups 3 0 0 0 4 AU1728, AU1323, AU1215, AU1009, AU0995, AU0658, AU0262DDX19A gdups 1 0 0 0 2 AU1551, AU1445, AU0686 DDX19B gdups 1 0 0 0 2AU1551, AU1445, AU0686 DEFB125 gdups 2 0 0 0 2 AU1534, AU1322 DGCR14gdups 3 0 4 0 3 AU0018, AU0991, AU0049 DGCR2 gdups 3 0 4 0 3 AU0018,AU0991, AU0049 DGCR6L gdups 2 0 3 0 2 AU0018, AU0049 DGCR8 gdups 3 0 4 03 AU0520, AU0018, AU0991, AU0049 DGKB edels 8 0 0 0 10 AU1400, AU1185,AU1074, AU0953, AU0767, AU0688, AU0399, AU0178, AU0110, AU1368, AU0289DHTKD1 gdups 1 0 0 3 2 AU0032 DHX29 edels 3 0 0 1 3 AU1823, AU1616,AU1054, AU0242 DHX34 edels 1 0 0 1 2 AU1685 DIDO1 edups 2 0 0 0 2AU0506, AU0099 DIDO1 gdups 4 0 0 0 4 AU0467, AU0099, AU0835, AU0676,AU0210 DKFZP686A10121 edels 2 0 0 3 3 AU0049, AU0030 DKFZP686E2158 gdups1 0 0 0 2 AU0293 DLGAP1 edels 4 0 0 0 5 AU1069, AU0952, AU0509, AU0453,AU0055, AU0052, AU0043 DNAJC10 edels 2 0 0 1 2 AU1798, AU0839, AU0134DNAJC15 edups 1 0 0 1 2 AU0043 DNAJC17 edups 7 0 0 0 13 AU1587, AU1399,AU1377, AU1211, AU1178, AU0958, AU0165 DOCK6 gdups 4 0 0 0 4 AU1193,AU1174, AU1164, AU0962, AU0934, AU0899, AU0520, AU0122, AU0991, AU0796DOT1L gdups 2 0 0 0 2 AU0991, AU0947, AU0298, AU0806, AU0676 DPP10 edels2 0 0 0 3 AU0543, AU0465 DSCR1 gdups 3 0 0 2 4 AU1510, AU1233, AU1227,AU1213, AU0753, AU0747, AU0661, AU1213, AU0158 DTX1 edels 1 0 0 1 2AU1171 DTX2 gdups 2 0 0 2 2 AU1632, AU0352, AU0314, AU0085 DUSP13 edups2 0 0 0 3 AU1327, AU1289, AU0085 DUSP7 gdups 1 0 0 0 2 AU1190 E2F4 gdups12 0 0 0 16 AU0939, AU0899, AU0610, AU0509, AU0450, AU0210, AU0028,AU1368, AU0991, AU0835 EBI3 gdups 2 0 0 0 2 AU1164, AU1099, AU0947,AU0934, AU0991 EDG5 gdups 3 0 0 0 3 AU1764, AU1174, AU1164, AU1963,AU0796 EDG6 gdups 2 0 0 0 2 AU1277, AU1174, AU0947, AU0622, AU0081,AU1534 EDG8 gdups 2 0 1 0 2 AU1273, AU1174, AU1164, AU0701, AU0866 EEF2gdups 7 0 0 0 7 AU1273, AU1193, AU1189, AU1164, AU1137, AU1072, AU0947,AU0932, AU0520, AU1216, AU0991, AU0866, AU0806, AU0688 EEFSEC gdups 1 00 0 2 AU0835 EFHA2 edels 2 0 0 0 3 AU1470, AU0477 EFHB edups 1 0 0 0 2AU0897 ELMO3 gdups 12 0 0 0 16 AU0939, AU0899, AU0610, AU0509, AU0450,AU0210, AU0028, AU1368, AU0991, AU0835 ELP4 edels 2 0 0 7 3 AU0905,AU0117, AU0290 EPHA10 edups 1 0 0 0 2 AU0616 EPRS edels 2 0 0 0 3AU1344, AU0053 EPX edups 1 0 0 0 2 AU0257 ERAS gdups 1 0 0 0 2 AU1465ERGIC1 edups 4 0 0 0 5 AU1368, AU1289, AU0899, AU0781 ESPN edels 1 0 0 82 AU1612, AU1301 EYA4 edups 1 0 0 0 2 AU1324 F2RL2 edels 1 0 0 0 3AU0980, AU0301 F9 edels 1 0 0 0 2 AU1823 FABP3 edels 1 0 0 0 3 AU0700FAM102A gdups 2 0 0 0 2 AU1174, AU0934, AU0866, AU0835 FAM110C edels 1 00 0 2 AU0385 FAM18B2 edels 1 0 0 1 2 AU0149 FAM18B2 gdups 1 0 0 0 2AU0707 FAM19A1 edels 1 0 1 0 2 AU0034 FAM19A4 edels 1 0 1 0 2 AU0034FAM20C gdups 1 0 0 0 2 AU0385 FAM21B gdups 2 0 0 1 2 AU1713, AU0845,AU0329 FAM43A gdups 1 0 0 0 2 AU0568 FAM81A gdups 1 0 0 0 2 AU0467,AU0236 FAM89B edels 3 0 1 0 4 AU1520, AU1439, AU1102 FANCL edups 1 0 0 02 AU1299, AU1296 FARSA edups 1 0 0 0 2 AU0599 FBXL8 gdups 1 0 0 0 2AU0962, AU0210 FCER2 gdups 1 0 0 0 2 AU1730 FGF13 edels 1 0 0 0 2 AU1823FGR edels 1 0 0 0 2 AU1798 FGR gdups 2 0 0 0 2 AU0783, AU0450, AU0085,AU0043, AU0008, AU1284 FHOD1 gdups 13 0 0 0 18 AU0939, AU0899, AU0722,AU0610, AU0509, AU0450, AU0210, AU0028, AU1368, AU0991, AU0899, AU0835FKSG24 gdups 3 0 0 0 3 AU1277, AU1174, AU0947, AU0520, AU0991, AU0866FLJ10379 gdups 2 0 0 2 3 AU1067, AU0821, AU0705, AU0640 FLJ11171 gdups 10 0 0 2 AU1551 FLJ11331 edels 1 0 0 6 2 AU1275, AU0603, AU0556 FLJ12529edups 6 0 0 0 12 AU1909, AU1640, AU1563, AU1327, AU1261, AU1072, AU0922,AU0199, AU0917 FLJ12949 edups 9 0 0 0 13 AU1406, AU1172, AU0920, AU0722,AU0689, AU0648, AU0629, AU0310, AU1187, AU1033, AU0806 FLJ14668 gdups 30 0 0 4 AU0722, AU0465, AU0149, AU0051 FLJ20323 edels 1 0 0 0 2 AU1105,AU0150 FLJ20487 gdups 1 0 0 0 2 AU0786 FLJ21865 edels 3 0 0 9 3 AU1779,AU1650, AU1286, AU1240, AU1332, AU0803 FLJ22671 edups 1 0 0 0 2 AU1244FLJ22688 gdups 2 0 1 0 2 AU1273, AU1072, AU0980, AU0880, AU0830, AU0753,AU0520, AU0068 FLJ25416 edels 1 0 0 0 2 AU1523, AU0246 FLJ25976 gdups 10 0 0 2 AU0755 FLJ37440 edups 1 0 0 0 3 AU1536, AU1163 FLJ38991 gdups 30 0 0 5 AU1462, AU1039, AU0551 FLJ41603 edups 3 0 0 0 5 AU1652, AU1486,AU1443, AU1389, AU0028 FLJ41993 gdups 3 0 0 0 3 AU1742, AU1368, AU1174,AU1055, AU0932, AU0916, AU0520, AU0991 FLJ43860 edups 3 0 0 0 3 AU1695,AU1374, AU1342, AU1102, AU0903, AU0763 FLJ44815 gdups 1 0 0 1 2 AU1559,AU0018 FLJ44894 edels 2 0 0 7 4 AU1559, AU1266, AU0686, AU0493, AU0208,AU0030 FLJ45831 edels 1 0 0 1 2 AU0149 FLJ45831 gdups 1 0 0 0 2 AU0707FLJ45850 gdups 2 0 0 0 2 AU1174, AU0934, AU0816, AU1527, AU0481 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edups 1 0 0 0 3 AU0733 WASF3 edups 5 0 0 1 8 AU1565,AU1054, AU1000, AU0610, AU0509, AU0138, AU0362 WDR18 edels 2 0 0 9 2AU1231, AU0809, AU1171 WDR71 edups 2 0 0 0 2 AU0997, AU0290 WDR73 edels1 0 0 0 3 AU0561 WDR78 edups 3 0 0 0 7 AU1916, AU1880, AU1791, AU1368WNT7A edups 3 0 0 0 4 AU0633, AU0121, AU0068 WWP2 edups 1 0 0 0 2 AU0718XG edels 2 0 0 0 4 AU1059, AU0338 XYLT1 edels 1 0 0 0 2 AU0791 YTHDF1edels 1 0 0 0 2 AU0746 ZBTB20 edels 1 0 0 0 2 AU1055 ZC3H7B edups 5 0 00 7 AU1582, AU1226, AU1158, AU1030, AU0947, AU0346, AU0017, AU1359ZCCHC14 edups 1 0 0 0 2 AU0771, AU0575 ZDHHC1 gdups 3 0 0 0 3 AU1207,AU0962, AU1368, AU0991, AU0835 ZDHHC11 edels 2 0 0 0 2 AU1185, AU1056,AU0951, AU1105 ZFAND2A gdups 1 0 0 1 2 AU1174, AU0922, AU0385 ZFP37edels 1 0 0 1 2 AU1247 ZFPM2 edels 1 0 0 0 2 AU0725, AU0452, AU0259 ZIC3edels 1 0 0 0 2 AU1823 ZMYND19 gdups 2 0 0 0 2 AU0767, AU0622 ZNF135edels 1 0 0 0 2 AU0179 ZNF141 edels 2 0 0 0 2 AU1251, AU1251, AU0032ZNF148 gdups 1 0 0 0 2 AU0911 ZNF208 edels 1 0 0 0 2 AU0145 ZNF208 gdups2 0 0 2 3 AU1338, AU1292 ZNF214 gdups 1 0 0 0 2 AU1309 ZNF215 gdups 1 00 0 2 AU1309 ZNF257 edels 2 0 0 1 3 AU1277, AU0145 ZNF324 gdups 2 0 0 02 AU1174, AU0934, AU0816, AU1527, AU0481 ZNF37A gdups 2 0 0 0 3 AU0257,AU1403 ZNF446 gdups 2 0 0 0 2 AU1174, AU0934, AU0816, AU1527, AU0481ZNF451 edels 1 0 1 0 2 AU1215 ZNF467 edups 2 0 0 0 2 AU0412, AU1048ZNF492 edels 1 0 0 0 2 AU0145 ZNF499 gdups 2 0 0 0 2 AU1164, AU0934,AU0816, AU0786 ZNF574 edels 2 0 0 5 2 AU1305, AU1286 ZNF592 edels 1 0 00 3 AU0561 ZNF650 edels 2 0 0 2 2 AU0767, AU0419, AU0264 ZNF676 edels 20 0 0 3 AU1277, AU0145 ZNF74 gdups 3 0 3 1 3 AU1334, AU0049, AU0018ZNF85 edels 2 0 0 1 2 AU0911, AU0809, AU0677, AU0201, AU0980 ZNF99 edels1 0 0 0 2 AU0145 ZSCAN2 edels 1 0 0 0 3 AU0561

TABLE 2 Description of AGRE sample used in the analysis. CHOP ControlCohort: 1110 samples genotyped 1070 retained after QC (96% pass rate)NINDS Control Cohort: 540 samples genotyped 418 retained after QC (77%pass rate) AGRE Family Cohort: 4163 samples genotyped on v3 arrays 3832retained after QC (92% pass rate) ACC Cases & Controls: see Glessner etal., 2009, Nature for a full description

TABLE 3 Summary of CNVs in AGRE cases, first-degree relatives, andunrelated controls. AGRE AGRE unaffected NINDS CHOP affected(siblings/parents) controls controls N= 1673 2159 418 1070 Mean # CNV24.7 25.2 20.5 23.3 Mean # eDels 2.0 2.1 2.3 2.6 Mean # eDups 6.0 6.32.2 4.2 Mean # gDups 4.0 4.1 1.0 2.5

TABLE 4 Shared by Region #SNP Length (bp) Type AGRE ID Scored statusInheritance status affected sibling? Previous reports 15q11-13 12465,902,313 dup AU010601 parent [22] 15q11-13 1246 5,902,313 dup AU010604Autism inherited No [22] 15q11-13 1246 5,902,313 dup AU1331202 parent15q11-13 1246 5,902,313 dup AU1331302 Autism inherited Yes 15q11-13 12465,902,313 dup AU1331303 Autism inherited Yes 15q11-13 1130 5,008,629 dupAU006501 parent 15q11-13 1130 5,008,629 dup AU006503 Spectrum inheritedYes AGRE cytogenetic annotation 15q11-13 1130 5,008,629 dup AU006504Autism inherited Yes AGRE cytogenetic annotation, [21] 15q11-13 11305,008,629 dup AU1135202 Autism de novo NA 15q11-13 1127 4,993,869 dupAU023303 Spectrum NA Yes [22] 15q11-13 1127 4,993,869 dup AU023304Autism NA Yes [21, 22] 15q11-13 1127 4,993,869 dup AU1607307 Autism denovo No 15q11-13 569 3,540,078 del AU1024202 parent 15q11-13 5693,540,078 del AU1024301 Autism inherited NA 15q11-13 437 1,347,744 dupAU038504 Autism de novo No [22] 15q11-13 287 1,578,642 dup AU1208301Autism de novo No 15q11-13 273 1,517,841 dup AU1875202 parent 15q11-1398 572,462 dup AU052003 Autism NA Yes [21] 15q11-13 96 572,462 dupAU052004 Autism NA Yes 16p11.2 47 530,466 del AU0154302 Autism de novoYes [10, 11] 16p11.2 47 530,466 del AU0154303 Autism de novo Yes [10,11, 21] 16p11.2 47 530,466 del AU029803 Autism de novo No [10, 11, 21]16p11.2 47 530,466 del AU041905 Autism de novo No [10, 11, 21] 16p11.247 530,466 del AU0938301 Autism de novo No [10, 11, 21] 16p11.2 47530,466 dup AU002901 parent [11] 16p11.2 47 530,466 dup AU002903 Autisminherited Yes [11] 16p11.2 47 530,466 dup AU002904 None inherited [11]16p11.2 47 530,466 dup AU002905 Autism inherited Yes [10, 11] 22q11.21512 2,534,567 dup AU001802 parent [22] 22q11.21 512 2,534,567 dupAU001804 Autism inherited No [21, 22] 22q11.21 512 2,534,567 dupAU004903 Autism de novo No [21, 22] 22q11.21 335 1,429,207 dup AU0991301Autism NA No 22q11.21 177 728,859 dup AU1334201 parent 22q11.21 177728,859 dup AU1334302 Spectrum inherited No 22q11.21 149 601,423 delAU1555302 Autism NA NA

TABLE 5 TaqMan primers and probes used in CNV validation.Reporter and reporter quencher are FAM and NFQ,respectively, unless noted AssaBSA15 Target = human BCL9forward primer = CTGAGTTGATTTTTGGTTAAGTTGATTCCTT (SEQ ID NO: 1)reverse primer = GGACCTGAAATTCGAGGATTCTGT (SEQ ID NO: 2)reporter sequence = TAGGAATGGGCATTAATAC (SEQ ID NO: 3) AssaBSA16Target = human NLRP3 forward primer = AGTGCAACCCAGGCTTTCTATTT(SEQ ID NO: 4) reverse primer = GTGTTTCTAACGCACTTTTTGTCTCA(SEQ ID NO: 5) reporter sequence = CAGACAACCTGTAAAAGC (SEQ ID NO: 6)AssaBSA20 Target = human NKX3-2 forward primer =TGGAAGCTCTATTCGCTGTATTTTTTCT (SEQ ID NO: 7) reverse primer =CCAAAAGTCGGGAAAAGACAGTTT (SEQ ID NO: 8) reporter sequence =CATGCCCTCCTGGACGC (SEQ ID NO: 9) AssaBSA21 Target = human HHIP-itgforward primer = TCATCTCAGTTGTGATCGTTCTGTTTT (SEQ ID NO: 10)reverse primer = AGGGTGTGCAGAAATGGTACTTAATT (SEQ ID NO: 11)reporter sequence = TCTACATCGTGAAATTAC (SEQ ID NO: 12) AssaBSA22Target = human 4q32.1 forward primer = TGAGTAACAGCATTTATCATGGCTTGA(SEQ ID NO: 13) reverse primer = GGAAAAGGTTTTGAAAACATTGTTATCACAGT(SEQ ID NO: 14) reporter sequence = CCTAAGATCAGGCAATTAG (SEQ ID NO: 15)AssaBSA23 Target = human 6q16.1 forward primer =AGTGACAGTACATGCAACAGTTCAT (SEQ ID NO: 16) reverse primer =GCTCCTCTGTAGCTGTCAGTTC (SEQ ID NO: 17) reporter sequence =CTGTGCCAAACTTCA (SEQ ID NO: 18) AssaBSA25 Target = human 8q21.2forward primer = AGTGTAGGTGCAATCAAAGAGAATGA (SEQ ID NO: 19)reverse primer = CTCAATTGTTTTAAAATATTGGGCAAAGTTCA (SEQ ID NO: 20)reporter sequence = ATAAGTGGTTTAGCATTTCTG (SEQ ID NO: 21) AssaBSA26Target = human HPSE2-in forward primer = TCAGTGAGGTCTGGGTTCAATATCT(SEQ ID NO: 22) reverse primer = TGCTGCTCATATGTTATCAAAGCATTATATCA(SEQ ID NO: 23) reporter sequence = TTGGCTGTCCGCCTTGT (SEQ ID NO: 24)AssaBSA27 Target = human TAT forward primer = GCTTCTTGGAGGCTGCTTTCT(SEQ ID NO: 25) reverse primer = CACCACTGCCTGATCAGCTT (SEQ ID NO: 26)reporter sequence = TTGGAAGGTAAAAATCTC (SEQ ID NO: 27) AssaBSA28Target = human PPP1R16B forward primer = CCAGCTGGTAATGTTGTCCTTCT(SEQ ID NO: 28) reverse primer = GAGAGTAGCACGGGCTTCT (SEQ ID NO: 29)reporter sequence = CACTCGCAGAACCCCA (SEQ ID NO: 30) AssaBSA29 Target =human BHLHB4 forward primer = GCGTAGCCGTGGCTTAGT (SEQ ID NO: 31)reverse primer = CCATGGCCGAGCTCAAGT (SEQ ID NO: 32) reporter sequence =CAGGTACGCGTCCCC (SEQ ID NO: 33) AssaBSA30 Target = human DMDforward primer = GATGGACTTCTTATCTGGATAGGTGGTA (SEQ ID NO: 34)reverse primer = GAGTCTCAAATATAGAAACCAAAAATTGATG TGT (SEQ ID NO: 35)reporter sequence = CAACATCTGTAAGCACATTAA (SEQ ID NO: 36) AssaBSA32Target = RNaseP endogenous control reporter = VIC; quencher =TAMRA, primer limited Part Number 4316844 (applied biosystems)

TABLE 6 gene class locus AGRE.Cases.Unrelated Map.Position.March.2006.Chr.Band ACRD? Combined.P ABCB9 gdups 120 3 chr12: 121979494-12202570512q24.31 Yes 0.07 ABCC1 edups 144 3 chr16: 15950935-16144432 16p13.11 No0.07 ACP6 gdups 15 3 chr1: 145585794-145608988 1q21.1 Yes 4.79E−03ADAMTS5 gdups 198 2 chr21: 27212112-27260703 21q21.3 No 0.17 ADAMTSL1edups 76 2 chr9: 18464098-18900948 9p22.2 No 0.17 ADCY1 edups 66 3 chr7:45580646-45729237 7p13 No 0.07 ADM2 gdups 208 4 chr22: 49266878-4927173222q13.33 Yes 0.03 AHR gdups 65 2 chr7: 17304832-17352294 7p21.1 Yes 0.37APBA3 gdups 173 3 chr19: 3701771-3712673 19p13.3 No 0.07 APLP1 gdups 1853 chr19: 41051241-41062539 19q13.12 Yes 0.07 ARHGEF16 edups 2 3 chr1:3361100-3387537 1p36.32 No 0.07 ARID3A edups 168 4 chr19: 877037-92378119p13.3 Yes 0.03 ARL11 gdups 123 4 chr13: 49100436-49106009 13q14.3 No0.03 ARSA gdups 208 4 chr22: 49410316-49413473 22q13.33 Yes 0.10 ARSDedels 209 2 chrX: 2832011-2857392 Xp22.33 Yes 0.17 ARSD gdups 209 2chrX: 2832011-2857392 Xp22.33 Yes 0.17 ARVCF gdups 203 4 chr22:18337421-18384309 22q11.21 Yes 8.05E−04 ASCC3 edups 55 3 chr6:101062791-101435961 6q16.3 No 0.07 ATCAY gdups 173 3 chr19:3831639-3873184 19p13.3 No 0.07 ATP10A gdups 132 6 chr15:23474952-23661412 15q12 Yes 9.28E−06 ATP6V0D1 gdups 149 3 chr16:66029418-66072590 16q22.1 No 0.07 BC002942 gdups 208 5 chr22:49288250-49292975 22q13.33 Yes 0.01 BCL9 gdups 15 3 chr1:145479806-145564641 1q21.1 Yes 4.79E−03 BTBD4 edups 197 3 chr20:61846322-61907300 20q13.33 Yes 0.07 BTN2A1 edels 53 2 chr6:26566168-26577844 6p22.1 No 0.37 BXDC1 edups 56 2 chr6:111409984-111453486 6q21 Yes 0.17 BZRAP1 edels 158 6 chr17:53733597-53760477 17q22 No 8.05E−04 BZRAP1 edups 158 4 chr17:53733597-53760477 17q22 No 0.03 C10orf72 edups 83 9 chr10:49896258-49993560 10q11.22 Yes 2.08E−03 C11orf72 gdups 102 3 chr11:67126927-67130753 11q13.2 No 0.07 C12orf38 gdups 121 2 chr12:122721644-122758901 12q24 Yes 0.17 C15orf2 gdups 132 6 chr15:22471634-22479686 15q11.2 Yes 3.79E−06 C19orf19 edels 167 3 chr19:414347-425983 19p13.3 No 1.35E−04 C1orf93 gdups 1 4 chr1:2508097-2512762 1p36.32 Yes 0.03 C1QTNF1 edels 163 8 chr17:74531846-74557465 17q25.3 No 0.17 C21orf51 gdups 201 3 chr21:34669619-34683322 21q22.11 No 0.34 C22orf25 gdups 203 3 chr22:18384537-18433449 22q11.21 Yes 1.96E−03 C22orf29 gdups 203 3 chr22:18213661-18222419 22q11.21 Yes 1.96E−03 C9orf28 edups 78 2 chr9:128128949-128309140 9q33.3 No 0.17 CA5A edups 152 3 chr16:86479126-86527613 16q24.2 Yes 0.07 CA6 edels 6 3 chr1: 8928509-89577331p36.23 No 0.03 CACHD1 edups 13 3 chr1: 64709063-64931329 1p31.3 No 0.07CACNA2D4 edups 108 5 chr12: 1771384-1898131 12p13.33 Yes 0.01 CAND2edels 34 2 chr3: 12813171-12851301 3p25.1 No 0.17 CARD11 edups 60 3chr7: 2912295-3050105 7p22.2 No 0.19 CARD9 gdups 81 5 chr9:138378229-138387954 9q34.3 Yes 4.79E−03 CBLN3 gdups 127 4 chr14:23965582-23968571 14q12 No 0.03 CBR1 gdups 202 2 chr21:36364155-36367332 21q22.12 Yes 0.17 CCL13 gdups 157 2 chr17:29707584-29709741 17q12 Yes 0.68 CD8A gdups 26 2 chr2: 86865240-868890302p11.2 No 0.07 CDC45L gdups 203 3 chr22: 17846982-17888135 22q11.21 Yes1.96E−03 CDH17 edels 73 2 chr8: 95208566-95289986 8q22.1 No 0.17 CEBPAgdups 184 3 chr19: 38482543-38485460 19q13.11 Yes 0.19 CELSR1 edups 2076 chr22: 45134397-45311731 22q13.31 Yes 4.79E−03 CENPT gdups 150 3chr16: 66419565-66425300 16q22.1 No 0.07 CERK edups 207 3 chr22:45458984-45512833 22q13.31 Yes 0.07 CERK gdups 207 5 chr22:45458984-45512833 22q13.31 Yes 0.01 CGB1 gdups 191 2 chr19:54230638-54231885 19q13.33 No 0.54 CGB2 gdups 191 2 chr19:54226942-54228307 19q13.33 No 0.54 CGB5 gdups 191 2 chr19:54238875-54240378 19q13.33 No 0.54 CGB8 gdups 191 2 chr19:54242709-54244212 19q13.33 No 0.54 CGI-38 gdups 149 3 chr16:65981213-65984922 16q22.1 No 0.07 CHD1L gdups 15 2 chr1:145180915-145234065 1q21.1 Yes 0.01 CHD9 edups 146 2 chr16:51646446-51918914 16q12.2 No 0.07 CLCNKA edels 9 4 chr1:16220953-16233132 1p36.13 No 0.03 CLDN17 gdups 199 2 chr21:30459753-30460945 21q21.3 No 0.17 CLDN5 gdups 203 3 chr22:17890547-17895068 22q11.21 Yes 1.96E−03 CLDN8 gdups 199 2 chr21:30508195-30510262 21q22.11 No 0.17 CLTCL1 gdups 203 3 chr22:17546989-17659239 22q11.21 Yes 1.96E−03 COL16A1 edups 11 5 chr1:31890435-31942507 1p35.2 No 0.05 COL27A1 edels 77 2 chr9:115957661-116114612 9q32 Yes 0.37 COMT gdups 203 3 chr22:18309256-18336539 22q11.21 Yes 1.96E−03 CORO7 gdups 143 4 chr16:4344546-4406572 16p13.3 No 0.03 COX4I1 gdups 151 3 chr16:84390697-84398109 16q24.1 No 0.07 CPNE7 edups 153 3 chr16:88169677-88191155 16q24.3 No 0.07 CREB3L3 gdups 173 9 chr19:4104629-4124050 19p13.3 No 3.30E−04 CRELD2 gdups 208 3 chr22:48698287-48707192 22q13.33 Yes 0.07 CSTF2T gdups 86 2 chr10:53125253-53129357 10q11.23 Yes 0.17 CYBASC3 gdups 98 2 chr11:60872856-60886305 11q12.2 No 0.17 CYP4A22 gdups 12 2 chr1:47375694-47388000 1p33 No 0.17 CYP4F22 edels 178 3 chr19:15497144-15524127 19p13.12 No 0.34 CYP4X1 gdups 12 2 chr1:47261827-47289009 1p33 No 0.17 CYP4Z1 gdups 12 2 chr1: 47305634-473565771p33 No 0.17 DACH1 edels 126 8 chr13: 70910099-71339331 13q21.33 No 0.24DAK gdups 98 4 chr11: 60857230-60872806 11q12.2 No 0.03 DAPK3 gdups 1737 chr19: 3909452-3920826 19p13.3 No 1.96E−03 DAZAP1 gdups 169 8 chr19:1358584-1386683 19p13.3 Yes 8.05E−04 DBH edups 79 2 chr9:135491306-135514287 9q34.2 Yes 0.17 DDB1 gdups 98 3 chr11:60823510-60857143 11q12.2 No 0.07 DGCR14 gdups 203 3 chr22:17497793-17512190 22q11.21 Yes 1.96E−03 DGCR2 gdups 203 3 chr22:17403795-17489967 22q11.21 Yes 1.96E−03 DGCR8 gdups 203 3 chr22:18447814-18479395 22q11.21 Yes 1.96E−03 DGKB edels 64 8 chr7:14151199-14909359 7p21.2 Yes 8.05E−04 DHX29 edels 46 3 chr5:54587831-54639278 5q11.2 No 0.19 DIDO1 gdups 194 4 chr20:60979535-61039719 20q13.33 Yes 0.03 DKFZP686A10121 edels 67 2 chr7:89813926-89854586 7q21.13 No 0.68 DLGAP1 edels 165 4 chr18:3486030-3870135 18p11.31 No 0.03 DNAJC17 edups 134 7 chr15:38847363-38886954 15q15.1 No 1.96E−03 DOCK6 gdups 177 4 chr19:11170973-11234157 19p13.2 No 0.03 DPP10 edels 28 2 chr2:114916346-116319798 2q14.1 Yes 0.17 DSCR1 gdups 201 3 chr21:34810654-34908615 21q22.12 No 0.34 DUSP13 edups 87 2 chr10:76524196-76538976 10q22.2 No 0.17 E2F4 gdups 148 12 chr16:65783569-65790322 16q22.1 No 2.27E−05 EDG5 gdups 174 3 chr19:10195520-10196581 19p13.2 No 0.07 EEF2 gdups 173 7 chr19:3927055-3936461 19p13.3 No 1.96E−03 EFHA2 edels 69 2 chr8:16929119-17024516 8p22 No 0.17 ELMO3 gdups 148 12 chr16:65790515-65795433 16q22.1 No 2.27E−05 ELP4 edels 95 2 chr11:31487873-31761903 11p13 No 0.94 EPRS edels 18 2 chr1:218208567-218286623 1q41 No 0.17 ERGIC1 edups 49 4 chr5:172193928-172312287 5q35.1 No 0.03 FAM89B edels 101 3 chr11:65096396-65098245 11q13.1 No 0.03 FHOD1 gdups 148 13 chr16:65820795-65838926 16q22.1 No 9.28E−06 FKSG24 gdups 180 3 chr19:18165040-18168550 19p13.11 No 0.07 FLJ10379 gdups 23 2 chr2:45469324-45691937 2p21 Yes 0.54 FLJ12529 edups 99 6 chr11:60926697-60953959 11q12.2 No 4.79E−03 FLJ12949 edups 175 9 chr19:10525267-10536683 19p13.2 No 3.30E−04 FLJ14668 gdups 25 3 chr2:70376612-70382724 2p14 Yes 0.07 FLJ21865 edels 163 3 chr17:74582614-74596276 17q25.3 No 0.93 FLJ38991 gdups 42 3 chr4:74140668-74154286 4q13.3 Yes 0.07 FLJ41603 edups 48 3 chr5:148941328-148994720 5q33.1 No 0.07 FLJ41993 gdups 208 3 chr22:48775069-48793182 22q13.33 Yes 0.07 FLJ43860 edups 74 3 chr8:142513111-142586512 8q24.3 No 0.07 FLJ44894 edels 181 2 chr19:20366360-20399602 19p12 No 0.94 FLRT1 gdups 100 6 chr11:63627938-63643221 11q13.1 No 4.79E−03 FLYWCH1 edels 141 3 chr16:2901981-2941209 16p13.3 No 4.79E−03 FMO5 gdups 15 2 chr1:145124462-145163569 1q21.1 Yes 0.01 FUT10 edups 71 3 chr8:33347884-33450206 8p12 No 0.07 GABRA5 gdups 132 5 chr15:24663151-24777095 15q12 Yes 2.27E−05 GABRB3 gdups 132 6 chr15:24339786-24767329 15q12 Yes 3.79E−06 GABRG3 gdups 132 5 chr15:24799263-25451622 15q12 Yes 5.54E−05 GALNT13 edels 31 4 chr2:154436672-155018734 2q23.3 Yes 0.01 GAMT gdups 169 8 chr19:1348089-1352552 19p13.3 Yes 8.05E−04 GEMIN4 edups 154 2 chr17:594411-602251 17p13.3 No 0.17 GGN gdups 186 4 chr19: 43566745-4357050819q13.2 No 0.03 GJA8 gdups 15 3 chr1: 145841560-145848017 1q21.1 Yes0.03 GMPS edels 38 3 chr3: 157071019-157138215 3q25.31 No 0.07 GNA11gdups 171 6 chr19: 3045408-3072452 19p13.3 Yes 4.79E−03 GNB1L gdups 2033 chr22: 18150747-18222462 22q11.21 Yes 1.96E−03 GNG7 edups 170 2 chr19:2465451-2506186 19p13.3 No 0.07 GOLGA8E gdups 130 2 chr15:20986537-20999858 15q11.2 Yes 0.17 GPR146 gdups 62 2 chr7:1061447-1065423 7p22.3 Yes 0.37 GPR89A gdups 15 3 chr1:144475774-144538430 1q21.1 No 0.03 GRIK5 edels 188 3 chr19:47194317-47261797 19q13.2 No 0.71 GSCL gdups 203 3 chr22:17516504-17517796 22q11.21 Yes 1.96E−03 GYG2 edels 209 2 chrX:2756859-2810858 Xp22.33 Yes 0.17 GYG2 gdups 209 2 chrX: 2756859-2810858Xp22.33 Yes 0.17 HES7 gdups 155 11 chr17: 7965024-7968127 17p13.1 No5.54E−05 HIRA gdups 203 3 chr22: 17698224-17799219 22q11.21 Yes 1.96E−03HNF4G edels 72 2 chr8: 76482732-76641600 8q21.11 No 0.17 HPCAL1 edups 224 chr2: 10360491-10485193 2p25.1 No 0.01 HSD11B2 gdups 149 3 chr16:66022537-66028953 16q22.1 No 0.07 HSPC171 gdups 148 13 chr16:65818517-65820683 16q22.1 No 9.28E−06 HTF9C gdups 203 3 chr22:18479398-18484768 22q11.21 Yes 1.96E−03 IFI30 gdups 180 4 chr19:18145579-18149927 19p13.11 No 0.03 INHBB gdups 30 3 chr2:120820189-120825853 2q14.2 No 0.07 ITGB1BP3 gdups 173 7 chr19:3884101-3893412 19p13.3 No 1.96E−03 KCNAB2 edups 3 5 chr1:5974113-6083840 1p36.31 No 4.79E−03 KCNE1 gdups 201 3 chr21:34740858-34806443 21q22.12 No 0.34 KCNE2 gdups 201 3 chr21:34658193-34665307 21q22.11 No 0.34 KCNH7 edups 32 2 chr2:162936163-163403274 2q24.2 No 0.17 KCNJ14 gdups 190 3 chr19:53650578-53661179 19q13.32 No 0.07 KCNQ1 edels 91 3 chr11:2422797-2826915 11p15.5 No 0.34 KCTD19 gdups 149 3 chr16:65880894-65918162 16q22.1 No 0.07 KCTD5 edups 140 5 chr16:2672499-2699030 16p13.3 No 0.01 KIAA0195 gdups 160 9 chr17:70964317-71007758 17q25.1 No 3.30E−04 KIAA0319 edups 52 5 chr6:24652311-24754362 6p22.2 No 0.01 KIAA0528 edels 113 2 chr12:22492808-22588719 12p12.1 No 0.78 KIAA1086 gdups 173 3 chr19:3755022-3820027 19p13.3 No 0.07 KIAA1586 edels 54 3 chr6:57019343-57027951 6p12.1 No 0.01 KIAA1856 edups 61 4 chr7:5312949-5429703 7p22.1 No 0.10 KLHL22 gdups 203 3 chr22:19125806-19180122 22q11.21 Yes 0.02 KREMEN2 edels 141 3 chr16:2954218-2958381 16p13.3 No 1.96E−03 KRTAP13-2 gdups 199 2 chr21:30665580-30666446 21q22.11 Yes 0.17 KRTAP23-1 gdups 199 2 chr21:30642598-30642795 21q22.11 Yes 0.17 KRTAP24-1 gdups 199 2 chr21:30575498-30577147 21q22.11 Yes 0.17 KRTAP26-1 gdups 199 2 chr21:30613313-30614505 21q22.11 Yes 0.17 KRTAP27-1 gdups 199 2 chr21:30631202-30631883 21q22.11 Yes 0.17 KRTHB1 gdups 114 3 chr12:50965964-50971566 12q13.13 No 0.19 LAMA2 edels 57 2 chr6:129245979-129879401 6q22.33 Yes 0.17 LFNG gdups 59 6 chr7:2518689-2535334 7p22.2 No 4.79E−03 LILRA3 gdups 192 4 chr19:59491666-59501764 19q13.42 No 0.64 LILRA5 gdups 192 4 chr19:59510165-59516221 19q13.42 No 0.64 LMTK3 gdups 190 4 chr19:53680340-53708258 19q13.32 No 0.03 LOC128977 gdups 203 3 chr22:17808417-17815220 22q11.21 Yes 1.96E−03 LOC150383 gdups 207 3 chr22:45018574-45024857 22q13.31 No 0.07 LOC162073 edels 145 3 chr16:19032783-19040453 16p12.3 No 0.07 LOC283849 gdups 148 12 chr16:65767006-65775384 16q22.1 No 2.27E−05 LOC285498 gdups 39 3 chr4:1056544-1097350 4p16.3 Yes 0.03 LOC388910 gdups 205 2 chr22:43343883-43346993 22q13.31 No 0.17 LOC389852 gdups 211 3 chrX:47871547-47876941 Xp11.23 Yes 0.07 LOC650137 edels 129 26 chr15:19915066-19915749 15q11.2 Yes 3.31E−11 LOC653319 gdups 148 10 chr16:65775770-65781608 16q22.1 No 1.35E−04 LOC728489 gdups 81 5 chr9:138376173-138378062 9q34.3 Yes 4.79E−03 LOC728912 gdups 15 3 chr1:146040948-146076705 1q21.1 Yes 0.01 LOC728932 gdups 15 3 chr1:145907791-145932379 1q21.1 Yes 0.01 LOC93343 gdups 179 5 chr19:17393714-17397140 19p13.11 No 0.01 LRBA edels 43 2 chr4:151405044-152156329 4q31.3 No 0.68 LRP3 gdups 184 3 chr19:38377330-38390383 19q13.11 Yes 0.07 LRP5 edups 104 3 chr11:67836684-67973315 11q13.2 No 0.07 LRRC27 edups 89 2 chr10:133995648-134109058 10q26.3 No 0.17 LRRC29 gdups 148 12 chr16:65798543-65818414 16q22.1 No 2.27E−05 LRRC36 gdups 149 3 chr16:65918248-65976604 16q22.1 No 0.07 LRTM2 gdups 109 3 chr12:1799956-1816179 12p13.33 Yes 0.07 LYG1 gdups 27 3 chr2:99267134-99287637 2q11.2 Yes 0.19 LYG2 gdups 27 3 chr2:99225141-99238034 2q11.2 Yes 0.19 MADCAM1 edels 167 3 chr19:447490-456340 19p13.3 No 5.54E−05 MAGEA11 gdups 212 2 chrX:148575479-148603920 Xq28 Yes 0.17 MAGEL2 gdups 131 5 chr15:21439789-21442268 15q11.2 Yes 9.28E−06 MAP2K2 gdups 173 7 chr19:4041319-4075126 19p13.3 No 1.96E−03 MAPK8IP1 gdups 96 5 chr11:45863778-45884592 11p11.2 No 0.01 MAST4 edels 47 2 chr5:65927932-66501179 5q12.3 No 0.17 MATK gdups 173 3 chr19: 3728968-375281019p13.3 No 0.07 MDGA2 edels 128 8 chr14: 46379045-47213703 14q21.3 No1.35E−04 METAP2 edups 117 2 chr12: 94391953-94433746 12q22 No 0.17MGC10992 edups 147 3 chr16: 56103591-56127978 16q13 No 0.07 MGC11335gdups 150 3 chr16: 66265940-66310720 16q22.1 No 0.07 MGMT edups 88 4chr10: 131155510-131455356 10q26.3 Yes 0.03 MIOX gdups 208 4 chr22:49272079-49275943 22q13.33 Yes 0.03 MKRN3 gdups 131 5 chr15:21361547-21364653 15q11.2 Yes 9.28E−06 MOCOS edups 166 3 chr18:32021478-32102682 18q12.2 No 0.07 MPDZ edels 75 2 chr9:13095703-13269563 9p23 Yes 0.37 MRPL40 gdups 203 3 chr22:17800036-17803594 22q11.21 Yes 1.96E−03 MRPL54 gdups 173 3 chr19:3713665-3718562 19p13.3 No 0.07 MSMB gdups 84 2 chr10: 51219559-5123259610q11.23 Yes 0.17 MUM1 gdups 169 4 chr19: 1300175-1329427 19p13.3 Yes0.03 MYLK2 gdups 193 2 chr20: 29870772-29886153 20q11.21 No 0.17 NBPF11gdups 15 3 chr1: 146040948-146076705 1q21.1 Yes 0.01 NCOA4 gdups 84 2chr10: 51235233-51260740 10q11.23 Yes 0.17 NDN gdups 131 5 chr15:21481916-21483570 15q11.2 Yes 2.27E−05 NDUFS7 gdups 169 4 chr19:1334906-1346583 19p13.3 Yes 0.03 NEK3 edups 124 2 chr13:51604780-51631997 13q14.3 No 0.17 NFIC edups 172 3 chr19:3310616-3414603 19p13.3 Yes 0.07 NRXN1 edels 24 5 chr2:50000992-51113178 2p16.3 Yes 3.30E−04 NUP210 edups 35 2 chr3:13332737-13436809 3p25.1 No 0.17 NUTF2 gdups 150 3 chr16:66438331-66462727 16q22.1 No 0.07 OBSCN edels 19 2 chr1:226462484-226633198 1q42.13 No 0.54 OCA2 gdups 132 5 chr15:25673622-26018053 15q13.1 Yes 2.27E−05 OPRD1 edups 10 5 chr1:29011241-29062795 1p35.3 No 0.01 OR1C1 edels 21 3 chr1:245987387-245988331 1q44 No 0.03 OR2AG1 edels 94 3 chr11:6762845-6763795 11p15.4 No 0.07 OR2AG2 edels 94 3 chr11: 6745814-674676411p15.4 No 0.07 OR4C6 gdups 97 4 chr11: 55186202-55190738 11q11 No 0.54OR4M2 edels 129 26 chr15: 19869940-19870881 15q11.2 Yes 3.31E−11 OR4N4edels 129 26 chr15: 19804548-19885172 15q11.2 Yes 1.35E−11 OR4S2 gdups97 9 chr11: 55174956-55175891 11q11 No 0.07 OSBPL5 edups 93 4 chr11:3064922-3143116 11p15.4 No 0.03 PAMCI edels 116 2 chr12:84722462-84754449 12q21.31 No 0.17 PAQR4 edels 141 3 chr16:2959343-2963484 16p13.3 No 1.96E−03 PCDH9 edels 125 2 chr13:65774970-66702578 13q21.32 Yes 0.17 PCQAP gdups 203 3 chr22:19191886-19248975 22q11.21 Yes 4.79E−03 PI4KA gdups 203 3 chr22:19391981-19543070 22q11.21 Yes 1.96E−03 PIK3R2 gdups 180 5 chr19:18125016-18142343 19p13.11 No 0.01 PIM3 gdups 208 3 chr22:48740165-48743721 22q13.33 Yes 0.07 PIP5K1C gdups 173 7 chr19:3581182-3651445 19p13.3 No 1.96E−03 PKMYT1 edels 141 3 chr16:2962793-2970506 16p13.3 No 1.96E−03 PLA2G4C edups 189 2 chr19:53242916-53305865 19q13.32 No 0.17 PLEKHG4 gdups 148 12 chr16:65868914-65880883 16q22.1 No 2.27E−05 PLEKHG5 edups 4 4 chr1:6448739-6502708 1p36.31 No 0.03 PLEKHM2 edels 8 3 chr1:15883414-15933849 1p36.21 No 0.34 POSTN edels 122 3 chr13:37034779-37070874 13q13.3 No 0.07 PP2447 edups 208 5 chr22:48966487-48980154 22q13.33 Yes 0.01 PP2447 gdups 208 8 chr22:48966487-48980154 22q13.33 Yes 8.05E−04 PPME1 edups 105 4 chr11:73619081-73643395 11q13.4 No 0.03 PRB3 edels 110 3 chr12:11311393-11313908 12p13.2 No 0.07 PRDM10 edups 107 3 chr11:129274817-129377940 11q24.3 No 0.07 PRIC285 edups 195 3 chr20:61659883-61676036 20q13.33 Yes 0.03 PRKAB2 gdups 15 2 chr1:145093314-145110753 1q21.1 Yes 0.01 PRKG1 edels 85 2 chr10:52421124-53728116 10q11.23 Yes 0.17 PROP1 gdups 51 3 chr5:177351842-177355849 5q35.3 No 0.07 PRR5 edups 206 3 chr22:43443257-43637329 22q13.31 No 0.07 PSCD2 gdups 190 4 chr19:53664424-53674457 19q13.32 No 0.03 PSKH1 gdups 150 4 chr16:66484705-66521078 16q22.1 No 0.03 PSMD8 gdups 186 2 chr19:43557016-43566304 19q13.2 No 0.17 QSOX2 edups 80 2 chr9:138238006-138277508 9q34.3 Yes 0.07 RAB35 edups 118 3 chr12:119017289-119038982 12q24.23 Yes 0.07 RAB39 gdups 106 2 chr11:107304487-107339416 11q22.3 No 0.37 RABGAP1L edels 16 2 chr1:172395171-173226353 1q25.1 No 0.99 RAI1 edups 156 5 chr17:17525512-17655492 17p11.2 Yes 0.01 RANBP1 gdups 203 3 chr22:18484947-18494878 22q11.21 Yes 1.96E−03 RANBP10 gdups 150 3 chr16:66314506-66398056 16q22.1 No 0.07 RAX2 gdups 173 3 chr19:3448813-3723219 19p13.3 No 0.07 RCD-8 gdups 150 4 chr16:66464500-66475907 16q22.1 No 0.03 RNF111 edups 136 3 chr15:57067157-57176541 15q22.1 Yes 0.07 RNF133 edels 68 3 chr7:122125078-122126208 7q31.32 Yes 0.03 RNF148 edels 68 3 chr7:122128956-122130257 7q31.32 Yes 0.03 RNF44 edups 50 5 chr5:175886306-175897027 5q35.2 No 0.05 RPS15 gdups 169 8 chr19:1389363-1391492 19p13.3 Yes 8.05E−04 RPS19 edups 187 3 chr19:47055828-47067322 19q13.2 No 0.07 RYR2 edups 20 3 chr1:235272128-236063911 1q43 No 0.34 SBF1 gdups 208 4 chr22:49232050-49260330 22q13.33 Yes 0.03 SETD4 gdups 202 2 chr21:36328709-36373557 21q22.12 Yes 0.17 SH3TC1 edups 41 2 chr4:8251960-8293725 4p16.1 No 0.07 SIRT4 edups 119 2 chr12:119224546-119235430 12q24.31 Yes 0.17 SKIV2L2 edels 46 6 chr5:54639594-54757163 5q11.2 No 0.02 SLC16A5 edups 159 3 chr17:70595650-70613841 17q25.1 No 0.07 SLC18A1 edels 70 2 chr8:20046652-20084997 8p21.3 No 0.17 SLC22A18 edups 92 3 chr11:2877527-2903052 11p15.4 No 0.03 SLC25A1 gdups 203 3 chr22:17543092-17546260 22q11.21 Yes 1.96E−03 SLC25A34 edels 8 3 chr1:15935396-15940471 1p36.21 No 0.34 SLC26A11 gdups 164 3 chr17:75808824-75841890 17q25.3 No 0.07 SLC28A1 edups 137 2 chr15:83228913-83290033 15q25.3 Yes 0.17 SLC2A4RG gdups 196 3 chr20:61841655-61845846 20q13.33 Yes 0.07 SLC45A1 edups 5 2 chr1:8300756-8326814 1p36.23 No 0.17 SLC6A15 edels 115 3 chr12:83777402-83830705 12q21.31 No 0.19 SLC7A10 gdups 184 3 chr19:38391410-38408596 19q13.11 Yes 0.07 SLC9A5 gdups 148 12 chr16:65840356-65863594 16q22.1 No 2.27E−05 SLCO1A2 edels 112 3 chr12:21311651-21439638 12p12.1 No 0.98 SLCO1B3 edups 111 2 chr12:20854905-20960925 12p12.2 No 0.17 SMARCA4 edups 176 2 chr19:10932606-11033953 19p13.2 No 0.17 SNRPN gdups 132 5 chr15:22619887-22776293 15q11.2 Yes 9.28E−06 SNURF gdups 132 5 chr15:22652824-22770696 15q11.2 Yes 9.28E−06 SNX25 edups 44 2 chr4:186368278-186527942 4q35.1 Yes 0.17 SPACA5B gdups 211 3 chrX:47875014-47876939 Xp11.23 Yes 0.07 SPON2 edels 40 5 chr4:1150725-1156602 4p16.3 Yes 0.11 SPRED3 gdups 186 4 chr19:43572779-43578711 19q13.2 No 0.03 SPRN gdups 90 2 chr10:135084160-135088111 10q26.3 Yes 0.37 SRL edups 142 3 chr16:4179378-4232077 16p13.3 No 0.07 SSSCA1 edels 101 3 chr11:65094519-65095793 11q13.1 No 0.03 SSX5 gdups 211 3 chrX:47930600-47941143 Xp11.23 Yes 0.07 STEAP3 edups 29 2 chr2:119697854-119739698 2q14.2 No 0.37 STIP1 gdups 100 5 chr11:63709873-63728596 11q13.1 No 0.01 SUCLG2 edels 37 2 chr3:67507835-67787728 3p14.1 Yes 0.07 SYNGR2 gdups 162 3 chr17:73676266-73680604 17q25.3 No 0.07 TCP10L gdups 200 3 chr21:32870733-32879714 21q22.11 No 0.07 THAP11 gdups 150 3 chr16:66433714-66435598 16q22.1 No 0.07 TJP3 gdups 173 5 chr19:3672735-3701807 19p13.3 No 0.01 TMEM112 gdups 138 3 chr16: 843635-96098516p13.3 Yes 0.07 TMEM138 gdups 98 2 chr11: 60886432-60893254 11q12.2 No0.17 TNFRSF14 gdups 1 4 chr1: 2479153-2486757 1p36.32 Yes 0.03 TNFRSF8edups 7 3 chr1: 12046021-12126851 1p36.22 No 0.07 TPPP edels 45 8 chr5:712978-746510 5p15.33 Yes 4.61E−03 TRPM1 gdups 133 2 chr15:29080845-29181216 15q13.3 Yes 0.37 TRPT1 gdups 100 5 chr11:63747848-3750257 11q13.1 No 0.01 TSC2 edups 139 2 chr16: 2037991-207871316p13.3 No 0.17 TSNAXIP1 gdups 150 3 chr16: 66398511-66419471 16q22.1 No0.07 TSSK2 gdups 203 3 chr22: 17498790-17500134 22q11.21 Yes 1.96E−03TXNRD2 gdups 203 3 chr22: 18243040-18309359 22q11.21 Yes 1.96E−03 UBE2Oedups 161 4 chr17: 71897491-71960883 17q25.1 No 0.03 UBE3A gdups 132 5chr15: 23133489-23235221 15q11.2 Yes 9.28E−06 UBR1 edups 135 2 chr15:41022398-41185578 15q15.2 No 0.37 UFD1L gdups 203 3 chr22:17817701-17846726 22q11.21 Yes 1.96E−03 UGT1A5 edels 33 2 chr2:234191093-234346688 2q37.1 No 0.17 UNC93B1 edels 103 3 chr11:67515151-67528169 11q13.2 No 0.03 UNCX4.1 gdups 63 3 chr7:1239180-1242734 7p22.3 Yes 0.07 UNQ2446 gdups 150 4 chr16:66476282-66477772 16q22.1 No 0.03 URP2 gdups 100 5 chr11:63730782-63747939 11q13.1 No 0.01 USH2A edels 17 3 chr1:213862859-214663361 1q41 Yes 0.07 UTRN edups 58 2 chr6:144654566-145215859 6q24.2 Yes 0.17 VCX2 gdups 210 3 chrX:8097985-8099308 Xp22.31 No 0.07 VPS37B gdups 120 4 chr12:121915835-121946665 12q24.31 Yes 0.03 WASF3 edups 121 5 chr13:26029840-26161080 13q12.13 No 0.05 WDR78 edups 14 3 chr1:67051162-67163158 1p31.3 No 0.07 WNT7A edups 36 3 chr3:13835085-13896619 3p25.1 No 0.07 XG edels 209 2 chrX: 2680115-2743955Xp22.33 Yes 0.17 ZC3H7B edups 204 5 chr22: 40027475-40086053 22q13.2 Yes0.01 ZDHHC1 gdups 149 3 chr16: 65985829-66007878 16q22.1 No 0.07 ZNF208gdups 182 2 chr19: 21940737-21985561 19p12 Yes 0.54 ZNF257 edels 183 2chr19: 22027106-22064084 19p12 Yes 0.37 ZNF37A gdups 82 2 chr10:38423281-38452282 10p11.21 No 0.17 ZNF676 edels 183 2 chr19:22153743-22171593 19p12 Yes 0.17 ZNF74 gdups 203 3 chr22:19078418-19092752 22q11.21 Yes 0.02

While certain preferred embodiments of the present invention have beendescribed and specifically exemplified above, it is not intended thatthe invention be limited to such embodiments. Various modifications maybe made to the invention without departing from the scope and spiritthereof as set forth in the following claims.

1. A method for detecting a propensity for developing a neurologicaldisorder, the method comprising: detecting the presence of at least oneCNV in a target polynucleotide wherein if said CNV is present, saidpatient has an increased risk for developing a neurological disorder,wherein said deletion containing CNV is selected from the group of CNVsconsisting of CNVs set forth in Table
 6. 2. The method as claimed inclaim 1, wherein said at least one CNV is an edel selected from thegroup consisting of BZRAP1 Benzodiazapine receptor (peripheral)associated protein 1 17q22-q23 chr17:53733592-53761151, MDGA2 MAM domaincontaining glycosylphosphatidylinositol anchor 214q21.3chr14:46,170,380-47,422,368, CLCNKA chloride channel Kachr1:16221072-16233132, NTRK1 Neurotrophic tyrosine kinase, receptor,type 1 1q21-q22 chr1:155,013,407-155,202,154, USH2A Usher syndrome 2A(autosomal recessive, mild) 1q41 chr1:213,752,880-214,875,391, NRXN1Neurexin 1 2p16.3 chr2:49,712,184-51,360,413, GALNT13UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgal 2q23.3-q24.1chr2:153,854,689-155,600,757, GMPS Guanine monophosphate synthetase 3q24chr3:157,059,820-157,149,414, SPON2 Spondin 2, extracellular matrixprotein 4p16.3 chr4:1,124,285-1,183,034, LRBA LPS-responsive vesicletrafficking, beach and anchor containin4q31.3chr4:151,217,225-152,344,150, TPPP Tubulin polymerization promotingprotein 5p15.3 chr5:567,501-892,810, SKIV2L2 Superkiller viralicidicactivity 2-like 2 (S. cerevisiae) 5q11.2 chr5:54,522,183-54,873,752,KIAA1586 KIAA1586 6p12.1 chr6:56,980,593-57,066,702, BTN2A1Butyrophilin, subfamily 2, member A1 6p22.1 chr6:26566167-26577844,BXDC1 Brix domain containing 1 6q21 chr6:111409983-111453487, LAMA2Laminin, alpha 2 (merosin, congenital muscular dystrophy) 6q22-q23chr6:128,945,101-130,370,307, DGKB Diacylglycerol kinase, beta 90 kDa7p21.2 chr7:14,015,810-15,013,734, RNF133 Ring finger protein 1337q31.32 chr7:122,118,508-122, 132, 937, RNF148 Ring finger protein 1487q31.33 chr7:122,118,508-122, 132, 937, SLC18A1 Solute carrier family 18(vesicular monoamine), member 1 8p21.3 chr8:19,874,095-20,257,554,COL27A1 Collagen, type XXVII, alpha 1 9q32 chr9:115958051-116112796,OR2AG1 Olfactory receptor, family 2, subfamily AG, member 1 11p15.4chr11:6762845-6763795, OR2AG2 Olfactory receptor, family 2, subfamilyAG, member 2 11p15.4 chr11:6745814-6746764, SSSCA1 Sjogrensyndrome/scleroderma autoantigen 1 11q13.1 chr11:65094518-65095815,FAM89B Family with sequence similarity 89, member B 11q23chr11:65,094,554-65,100,079, PRB3 Proline-rich protein BstNI subfamily 312p13.2 chr12:11310124-11313908, KRT3 Keratin 3 12q12-q13chr12:51,444,040-51,501,855, SLC6A15 Solute carrier family 6, member 1512q21.3 chr12:83,670,976-83,958,489, DACH1 Dachshund homolog 1(Drosophila) 13q22 chr13:70910098-71339331, LOC650137 Seventransmembrane helix receptor 15q11.2 chr15:19,812,808-20,018,007, OR4M2Olfactory receptor, family 4, subfamily M, member 2 15q11.2chr15:19,812,808-20,018,007, OR4N4 Hypothetical L00727924 15q11.2chr15:19,812,808-20,018,007, LOC162073 hypothetical protein LOC16207316p12.3 chr16:19,008,005-19,060,144, DLGAP1 Discs, large (Drosophila)homolog-associated protein 1 18p11.3 chr18:3,393,512-3,965,460, FLJ44894Homo sapiens cDNA FLJ44894 fis, clone BRAMY3000692, m 19p12chr19:20,227,461-20,491,547, CYP4F22 Cytochrome P450, family 4,subfamily F, polypeptide 22 19p13.12 chr19:15480335-15524128, GRIK5Glutamate receptor, ionotropic, kainate 5 19q13.2chr19:47,126,828-47,329,282, GYG2 Glycogenin 2 Xp22.3chrX:2,656,547-2,925,352, XG Xg pseudogene, Y-linked 2 Xp22.33chrX:2,656,547-2,925,353, FGF13 Fibroblast growth factor 13 Xq26.3chrX:137,421,326-138,459,367, SPANXB1 SPANX family, member B2 Xq27.1chrX:139,908,245-139,941,724, and SPANXB2 SPANX family, member B2 Xq27.1chrX:139,908,245-139,941,724.
 3. The method of claim 1, wherein saidneurological disorder is selected from the group consisting of autism,autism spectrum disorder (ASD), schizophrenia, bipolar disorder,Tourette Syndrome, and obsessive compulsive disorder.
 4. The method ofclaim 2, wherein said disorder is autism spectrum disorder.
 5. Themethod as claimed in claim 1, wherein the target nucleic acid isamplified prior to detection.
 6. The method of claim 1, wherein the stepof detecting the presence of said CNV is performed using a processselected from the group consisting of detection of specifichybridization, measurement of allele size, restriction fragment lengthpolymorphism analysis, allele-specific hybridization analysis, singlebase primer extension reaction, and sequencing of an amplifiedpolynucleotide.
 7. The method as claimed in claim 1 or 2, wherein in thetarget nucleic acid is DNA.
 8. The method of claim 1, wherein nucleicacids comprising said CNV are obtained from an isolated cell of thehuman subject.
 9. A method for identifying therapeutic agents whichalter neuronal signaling and/or morphology, comprising a) providingcells expressing at least one CNV as claimed in claim 1; b) providingcells which express the cognate wild type sequences corresponding to theCNV of step a); c) contacting the cells of steps a) and b) with a testagent and d) analyzing whether said agent alters neuronal signalingand/or morphology of cells of step a) relative to those of step b),thereby identifying agents which alter neuronal signaling andmorphology.
 10. The method of claim 9 wherein said agent has efficacyfor the treatment of neurodevelopmental disorders.
 11. A test agentidentified by claim 9 in a pharmaceutically acceptable carrier.
 12. Amethod for the treatment of a neurological disorder in a patient in needthereof comprising administration of an effective amount of the agent ofclaim
 11. 13. The method of claim 9, wherein said agent modulatesneuronal cell signaling.
 14. A vector comprising at least one of theCNV-containing nucleic acids of claim
 1. 15. A host cell comprising thevector of claim
 14. 16. A solid support comprising the neurologicaldisorder related CNV containing nucleic acid of claim
 1. 17. The methodof claim 9, wherein said CNV is an edel in MDGA2 or BZRAP1 or MDGA2. 18.The method of claim 9, wherein said CNV is an edel in NRXN1.
 19. Themethod of claim 9, wherein said CNV is an edel in GRIK5.